Methods of Administering Monomethyl Fumarate and Prodrugs Thereof Having Reduced Side Effects

ABSTRACT

Methods of reducing undesirable side effects during therapeutic treatment using monomethyl fumarate and prodrugs of monomethyl fumarate are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application Ser. No. 61/800,132, filed Mar. 15, 2013;61/692,168, filed Aug. 22, 2012; 61/713,897, filed Oct. 15, 2012;61/733,234, filed Dec. 4, 2012; 61/769,513, filed Feb. 26, 2013;61/841,513, filed Jul. 1, 2013; 61/692,174, filed Aug. 22, 2012;61/713,961, filed Oct. 15, 2012; and 61/837,796, filed Jun. 21, 2013;the contents of each of which are incorporated herein by reference intheir entirety.

TECHNICAL FIELD

Disclosed herein are methods of reducing patient flushing whileadministering monomethyl fumarate and/or a prodrug thereof during thetreatment of diseases such as multiple sclerosis and psoriasis.

BACKGROUND

Fumaric acid esters (FAEs) are approved in Germany for the treatment ofpsoriasis, are being evaluated in the United States for the treatment ofpsoriasis and multiple sclerosis, and have been proposed for use intreating a wide range of immunological, autoimmune, and inflammatorydiseases and conditions.

FAEs and other fumaric acid derivatives have been proposed for use intreating a wide-variety of diseases and conditions involvingimmunological, autoimmune, and/or inflammatory processes includingpsoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat. No. 6,277,882;Mrowietz and Asadullah, Trends Mol Med 2005, 111(1), 43-48; and Yazdiand Mrowietz, Clinics Dermatology 2008, 26, 522-526); asthma and chronicobstructive pulmonary diseases (Joshi et al., WO 2005/023241 and US2007/0027076); cardiac insufficiency including left ventricularinsufficiency, myocardial infarction and angina pectoris (Joshi et al.,WO 2005/023241; Joshi et al., US 2007/0027076); mitochondrial andneurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease, Huntington's disease, retinopathia pigmentosa and mitochondrialencephalomyopathy (Joshi and Strebel, WO 2002/055063, US 2006/0205659,U.S. Pat. Nos. 6,509,376, 6,858,750, and 7,157,423); transplantation(Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. Nos.6,359,003, 6,509,376, and 7,157,423; and Lehmann et al., Arch DermatolRes 2002, 294, 399-404); autoimmune diseases (Joshi and Strebel, WO2002/055063, U.S. Pat. Nos. 6,509,376, 7,157,423, and US 2006/0205659)including multiple sclerosis (MS) (Joshi and Strebel, WO 1998/52549 andU.S. Pat. No. 6,436,992; Went and Lieberburg, US 2008/0089896; Schimrigket al., Eur J Neurology 2006, 13, 604-610; and Schilling et al., ClinExperimental Immunology 2006, 145, 101-107); ischemia and reperfusioninjury (Joshi et al., US 2007/0027076); AGE-induced genome damage(Heidland, WO 2005/027899); inflammatory bowel diseases such as Crohn'sdisease and ulcerative colitis; arthritis; and others (Nilsson et al.,WO 2006/037342 and Nilsson and Muller, WO 2007/042034).

Fumaderm®, an enteric coated tablet containing a mixture of salts ofmonoethyl fumarate and dimethyl fumarate was approved in Germany in 1994for the treatment of psoriasis. Dimethyl fumarate (DMF) is rapidlymetabolized in vivo to monomethyl fumarate (MMF), and hence DMF isconsidered to be a prodrug of MMF.

Fumaderm® is dosed three times per day with 1-2 grams/day administeredfor the treatment of psoriasis. Fumaderm® exhibits a high degree ofinterpatient variability with respect to drug absorption and foodstrongly reduces bioavailability. Absorption is thought to occur in thesmall intestine with peak levels achieved 5-6 hours after oraladministration. Significant side effects occur in 70-90% of patients(Brewer and Rogers, Clin Expt'l Dermatology 2007, 32, 246-49; andHoefnagel et al., Br J Dermatology 2003, 149, 363-369). Side effects ofcurrent FAE therapy include gastrointestinal upset including nausea,vomiting, and diarrhea; and transient flushing of the skin. Inparticular, significant flushing incidences have been reported inpatients with psoriasis after administration of BG00012 (DMF) (Artuc etal., Br J Dermatology Preprint, 2006, 154, 21). Artuc et al. foundflushing incidences in 18 of 24 patients dosed. They also observedincreases in PGD₂, PGF₂, and serotonin plasma levels. The skin flushingside effect of FAEs is thought to be the result of interactions with thehydroxy-carboxylic acid receptor, HCA₂, on keratinocytes, as well as onLangerhans cells in the skin (Blad et al., Biological andPharmacological Roles of HCA Receptors, Advances in Pharmacology, 2011,62, 219-250).

Fumaric acid derivatives (Joshi and Strebel, WO 2002/055063, US2006/0205659, and U.S. Pat. No. 7,157,423 (amide compounds andprotein-fumarate conjugates); Joshi et al., WO 2002/055066 and Joshi andStrebel, U.S. Pat. No. 6,355,676 (mono and dialkyl esters); Joshi andStrebel, WO 2003/087174 (carbocyclic and oxacarbocylic compounds); Joshiet al., WO 2006/122652 (thiosuccinates); Joshi et al., US 2008/0233185(dialkyl and diaryl esters); Nielsen and Bundgaard, J Pharm Sci 1988,77(4), 285-298 (glycolamide ester prodrugs); and Nilsson et al., US2008/0004344 (salts)) have been developed in an effort to overcome thedeficiencies of current FAE therapy. Controlled release pharmaceuticalcompositions comprising fumaric acid esters are disclosed by Nilsson andMiller, WO 2007/042034; by Nilsson and Rupp, US 2012/0034274 and US2012/0034303. These last two publications describe FAE formulationsexhibiting reduced flushing in patients.

SUMMARY

Disclosed herein are methods of systemically administering atherapeutically effective amount of a compound selected from (i)monomethyl fumarate (MMF), (ii) a prodrug of monomethyl fumarate, and(iii) a combination thereof, to treat a disease in each patient of apopulation of patients in need of such treatment. The methods compriseadministering the compound(s) to each patient to achieve across thepopulation of patients a maximum average concentration, as definedherein, of monomethyl fumarate in the blood plasma of the patients ofless than 500 ng/ml. In certain aspects, the maximum averageconcentration of monomethyl fumarate in the blood plasma of the patientsis maintained at less than 400 ng/ml.

The methods further comprise administering the compound(s) to eachpatient to achieve, across the population of patients, an average Cmax,as defined herein, of monomethyl fumarate in the blood plasma of thepatients of less than 1100 ng/ml. In certain aspects, the average Cmaxof monomethyl fumarate in the blood plasma of the patients is maintainedat less than 600 ng/ml. In other aspects, the average Cmax of monomethylfumarate in the blood plasma of the patients is maintained at less than400 ng/ml.

The methods are effective in reducing the incidence/frequency offlushing across the population of patients.

Also disclosed herein are methods of systemically administering atherapeutically effective amount of a compound selected from (i)monomethyl fumarate (MMF), (ii) a prodrug of monomethyl fumarate, and(iii) a combination thereof, to treat a disease in each patient in apopulation of patients in need of such treatment. The methods compriseadministering the compound(s) to each patient to achieve across thepopulation of patients: an average maximum rate of rise in monomethylfumarate concentration in the blood plasma of the patients of less than0.25 wt % ng-eq of MMF dosed/ml/hr. In certain aspects, the averagemaximum rate of rise in monomethyl fumarate concentration is less than0.20 wt % ng-eq of MMF dosed/ml/hr. In other aspects, the averagemaximum rate of rise in monomethyl fumarate concentration is less than0.15 wt % ng-eq of MMF dosed/ml/hr. In other aspects, the averagemaximum rate of rise in monomethyl fumarate concentration is less than500 ng/mL/hr. In other aspects, the average maximum rate of rise inmonomethyl fumarate concentration is less than 400 ng/mL/hr. In otheraspects, the average maximum rate of rise in monomethyl fumarateconcentration is less than 250 ng/mL/hr. In other aspects, the averagemaximum rate of rise in monomethyl fumarate concentration is less than200 ng/mL/hr. In other aspects, the average maximum rate of rise inmonomethyl fumarate concentration is less than 180 ng/mL/hr. In otheraspects, the average maximum rate of rise in monomethyl fumarateconcentration is less than 140 ng/mL/hr.

In some embodiments, the methods comprise administering the compound(s)to each patient in a population of patients to achieve across thepopulation an average maximum rate of rise in monomethyl fumarateconcentration in the blood plasma of the patients of less than 0.25 wt %ng-eq of MMF dosed/ml/hr, and an average monomethyl fumarateconcentration in the blood plasma of the patients, measured at a time ofsaid maximum rate of rise, of less than 250 ng/ml. In anotherembodiment, the average maximum rate of rise in monomethyl fumarateconcentration in the blood plasma of the patients is less than 0.15 wt %ng-eq of MMF dosed/ml/hr, and an average monomethyl fumarateconcentration in the blood plasma of the patients, measured at a time ofsaid maximum rate of rise, is less than 200 ng/ml. In yet anotherembodiment, the average maximum rate of rise in monomethyl fumarateconcentration in the blood plasma of the patients is less than 0.10 wt %ng-eq of MMF dosed/ml/hr, and an average monomethyl fumarateconcentration in the blood plasma of the patients, measured at a time ofsaid maximum rate of rise, is less than 140 ng/ml.

Also disclosed herein are methods of systemically administering atherapeutically effective amount of a compound selected from (i)monomethyl fumarate (MMF), (ii) a prodrug of monomethyl fumarate, and(iii) a combination thereof, to treat a disease in a patient in need ofsuch treatment, comprising one of: (a) orally administering to thepatient, at a dosing frequency of not more than twice per day, anenteric-coated oral or a non-enteric-coated sustained release dosageform containing a therapeutically effective dose of the compound(s),wherein the dosage form, when subjected to an in vitro dissolution testemploying as a dissolution medium 750 mL of 0.1 N hydrochloric acid, atpH 1.2, for a period of 2 hours, followed by addition of 250 mL of 200mM tribasic sodium phosphate buffer resulting in an adjustment of the pHof the dissolution medium to 6.8, the dissolution medium beingmaintained at 37° C. and stirred at 100 rpm, releases: (i) less than 10wt % of the dose over an initial 2 hours of the in vitro dissolutiontest; (ii) at least 90 wt % of the dose over not less than an initial 8hours of the in vitro dissolution test; (iii) no more than 30 wt % ofthe dose in any one hour during the in vitro dissolution test; and (iv)no more than 40 wt % of the dose in any consecutive two hours during thein vitro dissolution test; or (b) orally administering to the patient,at a frequency of not more than twice per day, a non-enteric-coated oralsustained release dosage form containing a therapeutically effectivedose of the compound(s), wherein the dosage form, when subjected to anin vitro dissolution test employing as a dissolution medium 750 mL of0.1 N hydrochloric acid, at pH 1.2, for a period of 2 hours, followed byaddition of 250 mL of 200 mM tribasic sodium phosphate buffer resultingin an adjustment of the pH of the dissolution medium to 6.8, releases(i) at least 90 wt % of the dose over not less than an initial 8 hoursof the in vitro dissolution test; (ii) no more than 30 wt % of the dosein any one hour during the in vitro dissolution test; and (iii) no morethan 40 wt % of the dose in any consecutive two hours during the invitro dissolution test.

The therapeutic treatments disclosed herein can be used to treat anynumber of diseases for which FAEs are known or thought to betherapeutically effective. In certain embodiments, the therapeutictreatments disclosed herein can be used to treat adrenal leukodystrophy,AGE-induced genome damage, Alexanders Disease, Alper's Disease,Alzheimer's disease, amyotrophic lateral sclerosis, angina pectoris,arthritis, asthma, balo concentric sclerosis, Canavan disease, cardiacinsufficiency including left ventricular insufficiency, central nervoussystem vasculitis, Charcott-Marie-Tooth Disease, childhood ataxia withcentral nervous system hypomyelination, chronic idiopathic peripheralneuropathy, chronic obstructive pulmonary disease, Crohn's disease,diabetic retinopathy, graft versus host disease, hepatitis C viralinfection, herpes simplex viral infection, human immunodeficiency viralinfection, Huntington's disease, irritable bowel disorder, ischemia,Krabbe Disease, lichen planus, macular degeneration, mitochondrialencephalomyopathy, monomelic amyotrophy, multiple sclerosis, myocardialinfarction, neurodegeneration with brain iron accumulation,neuromyelitis optica, neurosarcoidosis, NF-κB mediated diseases, opticneuritis, pareneoplastic syndromes, Parkinson's disease,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, psoriasis, reperfusion injury, retinopathiapigmentosa, Schilders Disease, subacute necrotizing myelopathy, susacsyndrome, transplantation rejection, transverse myelitis, a tumor,ulcerative colitis, Zellweger's syndrome, granulomas includingannulaire, pemphigus, bollus pemphigoid, behcet's, contact dermatitis,acute dermatitis, chronic dermatitis, alopecia areata (totalis anduniversalis), sarcoidosis, cutaneous sarcoidosis, pyoderma gangrenosum,cutaneous lupus, Crohn's disease or cutaneous Crohn's disease. In someembodiments, the therapeutic treatments disclosed herein can be used forthe treatment of multiple sclerosis and psoriasis.

In a first aspect, the compound being administered comprises monomethylfumarate.

In a second aspect, the compound being administered comprises a prodrugof monomethyl fumarate.

In a third aspect, the prodrug of monomethyl fumarate comprises acompound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ is chosen froma C₁ to C₆ alkyl.

In a fourth aspect, the prodrug of monomethyl fumarate comprises acompound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R² and R³ are independently chosen from hydrogen, C₁₋₆ alkyl, andsubstituted C₁₋₆ alkyl;

R⁴ and R⁵ are independently chosen from hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, substituted C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, substituted C₁₋₆ alkoxycarbonyl, C₁₋₆ heteroalkyl,substituted C₁₋₆ heteroalkyl, C₄₋₁₂ cycloalkylalkyl, substituted C₄₋₁₂cycloalkylalkyl, C₇₋₁₂ arylalkyl, and substituted C₇₋₁₂ arylalkyl; or R⁴and R⁵ together with the nitrogen to which they are bonded form a ringchosen from a C₅₋₁₀ heteroaryl, substituted C₅₋₁₀ heteroaryl, C₅₋₁₀heterocycloalkyl, and substituted C₅₋₁₀ heterocycloalkyl; and whereineach substituent group is independently chosen from halogen, —OH, —CN,—CF₃, ═O, —NO₂, benzyl, —C(O)NR¹¹ ₂, —R¹¹, —OR¹¹, —C(O)R¹¹, —COOR¹¹, and—NR¹¹ ₂ wherein each R¹¹ is independently chosen from hydrogen and C₁₋₄alkyl.

In a fifth aspect, the prodrug of monomethyl fumarate comprises acompound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R⁶ is chosen from C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₁₋₆ heteroalkyl,substituted C₁₋₆ heteroalkyl, C₃₋₈ cycloalkyl, substituted C₃₋₈cycloalkyl, C₆₋₈ aryl, substituted C₆₋₈ aryl, and —OR¹⁰ wherein R¹⁰ ischosen from C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,substituted C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and substituted C₆₋₁₀ aryl;

R⁷ and R⁸ are independently chosen from hydrogen, C₁₋₆ alkyl, andsubstituted C₁₋₆ alkyl; and wherein each substituent group isindependently chosen from halogen, —OH, —CN, —CF₃, ═O, —NO₂, benzyl,—C(O)NR¹¹ ₂, —R¹¹, —OR¹¹, —C(O)R¹¹, —COOR, —N(R¹¹)C(O)C(R¹¹)₂NR¹¹ ₂, and—NR¹¹ ₂ wherein each R¹¹ is independently chosen from hydrogen and C₁₋₄alkyl.

In a sixth aspect, the prodrug of monomethyl fumarate comprises acompound of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein n is an integerfrom 2 to 6.

FIGURES

FIG. 1 shows the in vitro release profile of an enteric-coated sustainedreleased tablet according to Example 1.

FIG. 2 shows the mean plasma concentration of MMF following the oraldosing of an enteric-coated sustained released tablet according toExample 1.

FIG. 3 shows the percent of prodrug released from the Example 5 dosageforms over time.

FIG. 4 shows the mean plasma concentration of MMF following oral dosingof a formulation prepared according to Example 6 to fasted and fedhealthy adult patients.

FIG. 5 shows the percent of prodrug released from the Example 8 dosageforms over time.

FIG. 6 shows the percent of prodrug released from the Example 9 dosageforms over time.

FIG. 7 shows the percent of prodrug released from the Example 10 dosageforms over time.

FIG. 8 shows the percent of prodrug released from the two Example 12dosage forms over time.

FIG. 9 shows the percent of prodrug released from the two Example 13dosage forms over time.

FIG. 10 shows the percent of prodrug released from the Example 14 dosageform over time.

FIG. 11 shows the percent of prodrug released from the Example 15 dosageform over time.

FIG. 12 shows the mean plasma concentration of MMF following oral dosingof a formulation prepared according to Example 10 to fasted and fedhealthy adult patients.

FIG. 13 shows the % flushing incidences as a function of mean MMF Cmax(maximum average concentration) (ng/mL) over patient populations for DMFand Compound 1 (a prodrug of MMF).

FIG. 14 shows the % flushing incidences as a function of mean ofindividual MMF Cmax (average Cmax) (ng/mL) for DMF and Compound 1 (aprodrug of MMF).

FIG. 15 shows the % flushing incidences as a function of maximum MMFslope (% MMF ng-eq dose/mL/hr) for DMF and Compound 1 (a prodrug ofMMF).

FIG. 16 shows the % flushing incidences as a function of maximum MMFslope (ng/mL/hr) for DMF and Compound 1 (a prodrug of MMF).

The curves in the above figures, where applicable, were fitted using aHill E_(max) model.

Definitions

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a moiety or substituent. For example,—CONH₂ is bonded through the carbon atom.

“Alkyl” refers to a saturated or unsaturated, branched, orstraight-chain, monovalent hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane, alkene,or alkyne. Examples of alkyl groups include, but are not limited to,methyl; ethyls such as ethanyl, ethenyl, and ethynyl; propyls such aspropan-1-yl, propan-2-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such asbutan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds, and groupshaving combinations of single, double, and triple carbon-carbon bonds.Where a specific level of saturation is intended, the terms alkanyl,alkenyl, and alkynyl are used. In certain embodiments, an alkyl groupcan have from 1 to 20 carbon atoms (C₁₋₂₀) in certain embodiments, from1 to 10 carbon atoms (C₁₋₁₀), in certain embodiments from 1 to 8 carbonatoms (C₁₋₈), in certain embodiments, from 1 to 6 carbon atoms (C₁₋₆),in certain embodiments from 1 to 4 carbon atoms (C), and in certainembodiments, from 1 to 3 carbon atoms (C₁₋₃).

“Aryl” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Aryl encompasses benzene; bicyclic ring systemswherein at least one ring is carbocyclic and aromatic, for example,naphthalene, indane, and tetralin; and tricyclic ring systems wherein atleast one ring is carbocyclic and aromatic, for example, fluorene. Arylencompasses multiple ring systems having at least one carbocyclicaromatic ring fused to at least one carbocyclic aromatic ring,cycloalkyl ring, or heterocycloalkyl ring. For example, aryl includes aphenyl ring fused to a 5- to 7-membered heterocycloalkyl ring containingone or more heteroatoms chosen from N, O, and S. For such fused,bicyclic ring systems wherein only one of the rings is a carbocyclicaromatic ring, the radical carbon atom may be at the carbocyclicaromatic ring or at the heterocycloalkyl ring. Examples of aryl groupsinclude, but are not limited to, groups derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,hexalene, as-indacene, s-indacene, indane, indene, naphthalene,octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene,and the like. In certain embodiments, an aryl group can have from 6 to20 carbon atoms (C₆₋₂₀), from 6 to 12 carbon atoms (C₆₋₁₂), from 6 to 10carbon atoms (C₆₋₁₀), and in certain embodiments from 6 to 8 carbonatoms (C₆₋₈).

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl group. Examples of arylalkylgroups include, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylalkenyl, or arylalkynyl is used. In certainembodiments, an arylalkyl group is C₇₋₃₀ arylalkyl, e.g., the alkanyl,alkenyl or alkynyl moiety of the arylalkyl group is C₁₋₁₀ and the arylmoiety is C₆₋₂₀, in certain embodiments, an arylalkyl group is C₆₋₁₈arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkylgroup is C₁₋₈ and the aryl moiety is C₆₋₁₀. In certain embodiments, anarylalkyl group is C₇₋₁₂ arylalkyl.

“Compounds” of Formulae (I)-(IV) disclosed herein include any specificcompounds within these formulae. Compounds may be identified either bytheir chemical structure and/or chemical name. Compounds are named usingChemistry 4-D Draw Pro, version 7.01c (ChemInnovation Software, Inc.,San Diego, Calif.). When the chemical structure and chemical nameconflict, the chemical structure is determinative of the identity of thecompound. The compounds described herein may comprise one or more chiralcenters and/or double bonds and therefore may exist as stereoisomerssuch as double-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. Accordingly, any chemical structures within the scope ofthe specification depicted, in whole or in part, with a relativeconfiguration are deemed to encompass all possible enantiomers andstereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure, enantiomericallypure, or diastereomerically pure) and enantiomeric and stereoisomericmixtures. Enantiomeric and stereoisomeric mixtures may be resolved intotheir component enantiomers or stereoisomers using separation techniquesor chiral synthesis techniques well known to the skilled artisan.Compounds selected from monomethyl fumarate, or a prodrug of monomethylfumarate such as dimethyl fumarate or a compound of Formulae (I)-(IV),include, but are not limited to, optical isomers thereof, racematesthereof, and other mixtures thereof. In such embodiments, a singleenantiomer or diastereomer, i.e., optically active form can be obtainedby asymmetric synthesis or by resolution of the racemates. Resolution ofthe racemates may be accomplished, for example, by conventional methodssuch as crystallization in the presence of a resolving agent, orchromatography using, for example, chiral stationary phases.Notwithstanding the foregoing, in compounds selected from monomethylfumarate, or a prodrug of monomethyl fumarate such as dimethyl fumarateor a compound of Formulae (I)-(IV), the configuration of the illustrateddouble bond is only in the E configuration (i.e. trans configuration).

Compounds selected from monomethyl fumarate, or a prodrug of monomethylfumarate such as dimethyl fumarate or a compound of Formulae (I)-(IV),may also exist in several tautomeric forms including the enol form, theketo form, and mixtures thereof. Accordingly, the chemical structuresdepicted herein encompass all possible tautomeric forms of theillustrated compounds. Compounds selected from monomethyl fumarate, or aprodrug of monomethyl fumarate such as dimethyl fumarate or a compoundof Formulae (I)-(IV), also include isotopically labeled compounds whereone or more atoms have an atomic mass different from the atomic massconventionally found in nature. Examples of isotopes that may beincorporated into the compounds disclosed herein include, but are notlimited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Compounds mayexist in unsolvated forms as well as solvated forms, including hydratedforms and as N-oxides. In general, compounds as referred to herein maybe free acid, hydrated, solvated, or N-oxides. Certain compounds mayexist in multiple crystalline, co-crystalline, or amorphous forms.Compounds selected from monomethyl fumarate, or a prodrug of monomethylfumarate such as dimethyl fumarate or a compound of Formulae (I)-(IV),include pharmaceutically acceptable salts thereof, or pharmaceuticallyacceptable solvates of the free acid form of any of the foregoing, aswell as crystalline forms of any of the foregoing.

Compounds selected from monomethyl fumarate, or a prodrug of monomethylfumarate such as dimethyl fumarate or a compound of any of Formulae(I)-(IV), also include solvates. A solvate refers to a molecular complexof a compound with one or more solvent molecules in a stoichiometric ornon-stoichiometric amount. Such solvent molecules are those commonlyused in the pharmaceutical art, which are known to be innocuous to apatient, e.g., water, ethanol, and the like. A molecular complex of acompound or moiety of a compound and a solvent can be stabilized bynon-covalent intra-molecular forces such as, for example, electrostaticforces, van der Waals forces, or hydrogen bonds. The term “hydrate”refers to a solvate in which the one or more solvent molecules is water.

Further, when partial structures of the compounds are illustrated, anasterisk (*) indicates the point of attachment of the partial structureto the rest of the molecule.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylradical. Where a specific level of saturation is intended, thenomenclature cycloalkanyl or cycloalkenyl is used. Examples ofcycloalkyl groups include, but are not limited to, groups derived fromcyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. Incertain embodiments, a cycloalkyl group is C₃₋₁₅ cycloalkyl, C₃₋₁₂cycloalkyl, and in certain embodiments, C₃₋₈ cycloalkyl.

“Cycloalkylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with a cycloalkyl group. Where specific alkylmoieties are intended, the nomenclature cycloalkylalkanyl,cycloalkylalkenyl, or cycloalkylalkynyl is used. In certain embodiments,a cycloalkylalkyl group is C₄₋₃₀ cycloalkylalkyl, e.g., the alkanyl,alkenyl, or alkynyl moiety of the cycloalkylalkyl group is C₁₋₁₀ and thecycloalkyl moiety is C₃₋₂₀, and in certain embodiments, acycloalkylalkyl group is C₃₋₂₀ cycloalkylalkyl, e.g., the alkanyl,alkenyl, or alkynyl moiety of the cycloalkylalkyl group is C₁₋₈ and thecycloalkyl moiety is C₃₋₁₂. In certain embodiments, a cycloalkylalkylgroup is C₄₋₁₂ cycloalkylalkyl.

“Dimethyl fumarate” refers to the dimethyl ester of fumaric acid. Thecompound has the formula H₃COOCCH═CHCOOCH₃, and has a molecular weightof 144.13 daltons. This compound is also known by the names Dimethyl(E)-butenedioate (IUPAC), trans-1,2-Ethylenedicarboxylic acid dimethylester and (E)-2-Butenedioic acid dimethyl ester. The compound is alsoreferred to herein by the acronym DMF.

“Disease” refers to a disease, disorder, condition, or symptom of any ofthe foregoing.

“Drug” as defined under 21 U.S.C. § 321(g)(l) means “(A) articlesrecognized in the official United States Pharmacopoeia, officialHomeopathic Pharmacopoeia of the United States, or official NationalFormulary, or any supplement to any of them; and (B) articles intendedfor use in the diagnosis, cure, mitigation, treatment, or prevention ofdisease in man or other animals; and (C) articles (other than food)intended to affect the structure or any function of the body of man orother animals.

“Flushing” refers to a transient erythema or redness of the skin,together with a sensation of warmth or burning, typically over the faceand/or neck and less frequently on the upper trunk and abdomen. A flushis usually temporary and is caused by medications or other substancesthat cause widening of the capillaries, such as niacin. A more detaileddescription of flushing can be found in Champion R. H., et al, eds.Rook/Wilkinson/Ebling Textbook of Dermatology, 6th ed., vol. 3., Oxford,UK: Blackwell Scientific, 1998; “Flushing and Flushing Syndromes,Rosacea and Perioral Dermatitis”, pp. 2099-2104.

“Halogen” refers to a fluoro, chloro, bromo, or iodo group. In certainembodiments, halogen refers to a chloro group.

“Heteroalkyl” by itself or as part of another substituent refers to analkyl group in which one or more of the carbon atoms (and certainassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatomic groups. Examples of heteroatomic groups include,but are not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR¹³, ═N—N═,—N═N—, —N═N—NR¹³—, —PR¹³—, —P(O)₂—, —POR¹³—, —O—P(O)₂—, —SO—, —SO₂—,—Sn(R¹³)₂—, and the like, where each R¹³ is independently chosen fromhydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₆₋₁₂ aryl, substitutedC₆₋₁₂ aryl, C₇₋₁₈ arylalkyl, substituted C₇₋₁₈ arylalkyl, C₃₋₇cycloalkyl, substituted C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl,substituted C₃₋₇ heterocycloalkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆heteroalkyl, C₆₋₁₂ heteroaryl, substituted C₆₋₁₂ heteroaryl, C₇₋₁₈heteroarylalkyl, or substituted C₇₋₁₈ heteroarylalkyl. Reference to, forexample, a C₁₋₆ heteroalkyl, means a C₁₋₆ alkyl group in which at leastone of the carbon atoms (and certain associated hydrogen atoms) isreplaced with a heteroatom. For example C₁₋₆ heteroalkyl includes groupshaving five carbon atoms and one heteroatom, groups having four carbonatoms and two heteroatoms, etc. In certain embodiments, each R¹³ isindependently chosen from hydrogen and C₁₋₃ alkyl. In certainembodiments, a heteroatomic group is chosen from —O—, —S—, —NH—,—N(CH₃)—, and —SO₂—; and in certain embodiments, the heteroatomic groupis —O—.

“Heteroaryl” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Heteroaryl encompasses multiple ring systemshaving at least one heteroaromatic ring fused to at least one otherring, which can be aromatic or non-aromatic. For example, heteroarylencompasses bicyclic rings in which one ring is heteroaromatic and thesecond ring is a heterocycloalkyl ring. For such fused, bicyclicheteroaryl ring systems wherein only one of the rings contains one ormore heteroatoms, the radical carbon may be at the aromatic ring or atthe heterocycloalkyl ring. In certain embodiments, when the total numberof N, S, and O atoms in the heteroaryl group exceeds one, theheteroatoms are not adjacent to one another. In certain embodiments, thetotal number of heteroatoms in the heteroaryl group is not more thantwo.

Examples of heteroaryl groups include, but are not limited to, groupsderived from acridine, arsindole, carbazole, β-carboline, chromane,chromene, cinnoline, furan, imidazole, indazole, indole, indoline,indolizine, isobenzofuran, isochromene, isoindole, isoindoline,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, perimidine, phenanthridine, phenanthroline, phenazine,phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, thiazolidine, oxazolidine, and the like. In certainembodiments, a heteroaryl group is from 4- to 20-membered heteroaryl(C₄₋₂₀), and in certain embodiments from 4- to 12-membered heteroaryl(C₄₋₁₀). In certain embodiments, heteroaryl groups are those derivedfrom thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,quinoline, imidazole, oxazole, or pyrazine. For example, in certainembodiments, C₅ heteroaryl can be furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, isothiazolyl, isoxazolyl.

“Heterocycloalkyl” refers to a saturated or unsaturated cyclic alkylradical in which one or more carbon atoms (and certain associatedhydrogen atoms) are independently replaced with the same or differentheteroatom; or to a parent aromatic ring system in which one or morecarbon atoms (and certain associated hydrogen atoms) are independentlyreplaced with the same or different heteroatom such that the ring systemno longer contains at least one aromatic ring. Examples of heteroatomsto replace the carbon atom(s) include, but are not limited to, N, P, O,S, Si, etc. Examples of heterocycloalkyl groups include, but are notlimited to, groups derived from epoxides, azirines, thiiranes,imidazolidine, morpholine, piperazine, piperidine, pyrazolidine,pyrrolidine, quinuclidine, and the like. In certain embodiments, aheterocycloalkyl group is C₅₋₁₀ heterocycloalkyl, C₅₋₈ heterocycloalkyl,and in certain embodiments, C₅₋₆ heterocycloalkyl.

“Leaving group” has the meaning conventionally associated with it insynthetic organic chemistry, i.e., an atom or a group capable of beingdisplaced by a nucleophile and includes halogen such as chloro, bromo,fluoro, and iodo, acyloxy (alkoxycarbonyl) such as acetoxy andbenzoyloxy, aryloxycarbonyl, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy such as 2,4-dinitrophenoxy,methoxy, N,O-dimethylhydroxylamino, p-nitrophenolate, imidazolyl, andthe like.

“Monomethyl fumarate” refers to the monomethyl ester of fumaric acid.The compound has the formula HOOCCH═CHCOOCH₃, and has a molecular weightof 130.10 daltons. The compound is also commonly referred to as2(E)-Butenedioic acid 1-methyl ester, (2E)-4-Methoxy-4-oxobut-2-enoicacid; Fumaric acid hydrogen 1-methyl ester; (2E)-2-Butenedioic acid1-methyl ester; (E)-2-Butenedioic acid monomethyl ester; Monomethyltrans-ethylene-1,2-dicarboxylate; and methyl hydrogen fumarate. Thecompound is also referred to herein and elsewhere by the acronyms MMFand/or MHF.

“Parent aromatic ring system” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π (pi) electron system.Included within the definition of “parent aromatic ring system” arefused ring systems in which one or more of the rings are aromatic andone or more of the rings are saturated or unsaturated, such as, forexample, fluorene, indane, indene, phenalene, etc. Examples of parentaromatic ring systems include, but are not limited to, aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,hexalene, as-indacene, s-indacene, indane, indene, naphthalene,octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene,and the like.

“Parent heteroaromatic ring system” refers to an aromatic ring system inwhich one or more carbon atoms (and any associated hydrogen atoms) areindependently replaced with the same or different heteroatom in such away as to maintain the continuous r-electron system characteristic ofaromatic systems and a number of out-of-plane r-electrons correspondingto the Hückel rule (4n+2). Examples of heteroatoms to replace the carbonatoms include, but are not limited to, N, P, O, S, and Si, etc.Specifically included within the definition of “parent heteroaromaticring systems” are fused ring systems in which one or more of the ringsare aromatic and one or more of the rings are saturated or unsaturated,such as, for example, arsindole, benzodioxan, benzofuran, chromane,chromene, indole, indoline, xanthene, etc. Examples of parentheteroaromatic ring systems include, but are not limited to, arsindole,carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole,indazole, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene,thiazolidine, oxazolidine, and the like.

“Patient” refers to a mammal, for example, a human.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include acid addition salts, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; andsalts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine, andthe like. In certain embodiments, a pharmaceutically acceptable salt isthe hydrochloride salt. In certain embodiments, a pharmaceuticallyacceptable salt is the sodium salt.

“Pharmaceutically acceptable vehicle” refers to a pharmaceuticallyacceptable diluent, a pharmaceutically acceptable adjuvant, apharmaceutically acceptable excipient, a pharmaceutically acceptablecarrier, or a combination of any of the foregoing with which a compoundprovided by the present disclosure may be administered to a patient andwhich does not destroy the pharmacological activity thereof and which isnon-toxic when administered in doses sufficient to provide atherapeutically effective amount of the compound.

“Pharmaceutical composition” refers to a compound selected frommonomethyl fumarate, or a prodrug of monomethyl fumarate such asdimethyl fumarate or a compound of Formulae (I)-(IV), and at least onepharmaceutically acceptable vehicle, with which the compound isadministered to a patient.

“Substituted” refers to a group in which one or more hydrogen atoms areindependently replaced with the same or different substituent group(s).In certain embodiments, each substituent group is independently chosenfrom halogen, —OH, —CN, —CF₃, ═O, —NO₂, benzyl, —C(O)NH₂, —R¹¹, —OR¹¹,—C(O)R¹¹, —COOR¹¹, and —NR¹¹ ₂ wherein each R¹¹ is independently chosenfrom hydrogen and C₁₋₄ alkyl. In certain embodiments, each substituentgroup is independently chosen from halogen, —OH, —CN, —CF₃, —NO₂,benzyl, —R¹¹, —OR¹¹, and —NR¹¹ ₂ wherein each R¹¹ is independentlychosen from hydrogen and C₁₋₄ alkyl. In certain embodiments, eachsubstituent group is independently chosen from halogen, —OH, —CN, —CF₃,═O, —NO₂, benzyl, —C(O)NR¹¹ ₂, —R¹¹, —OR¹¹, —C(O)R¹¹, —COOR¹¹, and —NR¹²wherein each R¹¹ is independently chosen from hydrogen and C₁₋₄ alkyl.In certain embodiments, each substituent group is independently chosenfrom —OH, C₁₋₄ alkyl, and —NH₂.

“Systemic administration” and “systemically administering” shall eachmean a route of administration of a compound (as defined herein) intothe circulatory system of a patient in a therapeutically effectiveamount (as defined herein). In some non-limiting embodiments,administration can take place via enteral administration (absorption ofthe medication through the gastrointestinal tract) or parenteraladministration (generally injection, infusion, or implantation). Theseterms are in contrast with topical and other types of localadministration where a therapeutically effective amount is not in thecirculatory system. In some embodiments, systemic administration is oraladministration. In some embodiments, systemic administration isparenteral administration by injection.

“Treating” or “treatment” of any disease refers to reversing,alleviating, arresting, or ameliorating a disease or at least one of theclinical symptoms of a disease, reducing the risk of acquiring at leastone of the clinical symptoms of a disease, inhibiting the progress of adisease or at least one of the clinical symptoms of the disease orreducing the risk of developing at least one of the clinical symptoms ofa disease. “Treating” or “treatment” also refers to inhibiting thedisease, either physically, (e.g., stabilization of a discerniblesymptom), physiologically, (e.g., stabilization of a physicalparameter), or both, and to inhibiting at least one physical parameterthat may or may not be discernible to the patient. In certainembodiments, “treating” or “treatment” refers to protecting against ordelaying the onset of at least one or more symptoms of a disease in apatient.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease, or at leastone of the clinical symptoms of a disease, is sufficient to affect suchtreatment of the disease or symptom thereof. The “therapeuticallyeffective amount” may vary depending, for example, on the compound, thedisease and/or symptoms of the disease, severity of the disease and/orsymptoms of the disease or disorder, the age, weight, and/or health ofthe patient to be treated, and the judgment of the prescribingphysician. An appropriate amount in any given instance may beascertained by those skilled in the art or capable of determination byroutine experimentation.

“Therapeutically effective dose” refers to a dose that provideseffective treatment of a disease or disorder in a patient. Atherapeutically effective dose may vary from compound to compound, andfrom patient to patient, and may depend upon factors such as thecondition of the patient and the route of delivery. A therapeuticallyeffective dose may be determined in accordance with routinepharmacological procedures known to those skilled in the art.

“Average Cmax” refers to the average of two or more individual Cmaxvalues determined across a group of multiple subjects. For example, ifmultiple subjects are dosed as described herein they can each have adifferent individual Cmax value. The calculated mean of these differentCmax values is the “Average Cmax” for the group.

“Maximum Average Concentration” refers to the observed Cmax of anaverage plot of MMF concentration versus time for a group of subjects,constructed as a single curve using the calculated average MMFconcentration across all subjects at each time point. For example, if agroup comprising multiple subjects is dosed as described herein eachsubject can each have different MMF concentrations at any given timepoint. The observed Cmax value obtained from the single curveconstructed by plotting the average concentration values at each timepoint is the “Maximum Average Concentration”. The “Maximum AverageConcentration” value may not be the same as the “Average Cmax” value forthe same group of individuals.

“Average maximum rate of rise” refers to the average of all of theindividual maximum rates of rise determined across all subjects.

DETAILED DESCRIPTION

Reference is now made in detail to certain embodiments of the methodsfor reducing flushing in patients during administration of a compoundselected from: (i) monomethyl fumarate, (ii) a prodrug of monomethylfumarate, and/or (iii) a combination thereof. The disclosed embodimentsare not intended to be limiting of the claims. To the contrary, theclaims are intended to cover all alternatives, modifications, andequivalents.

Methods

In Vitro Measurement of MMF or MMF Prodrug Release from a Dosage Form

A 2-stage dissolution test in which the dosage form to be tested isfirst placed in a low pH solution for 2 hours, followed by placement ina near neutral pH solution for the remainder of the test period. Thisdissolution test is used to better approximate the pH conditionsexperienced by a dosage form after swallowing by a patient, i.e., low pHof the stomach followed by near neutral pH of the intestines. The dosageforms are first placed into a dissolution vessel (USP, Type I, basket)containing 750 mL of 0.1 N hydrochloric acid (pH 1.2). After 2 hours,250 mL of 200 mM tribasic sodium phosphate is added to the vesselresulting in a pH adjustment from 1.2 to 6.8. The dissolution medium iskept at 37° C. and is agitated at 100 rpm. Samples are taken at eachsampling time point and analyzed by reverse phase HPLC using a C18column for the compound being tested. The HPLC parameters are set asfollows: a 7 minute gradient method according to Table 4 (Example 2)where Mobile Phase A is water/0.1% H₃PO₄ and Mobile Phase B iswater/acetonitrile/H₃PO₄ (10/90/0.1 by volume) with UV detection at 210nm.

Individual patients exhibit varying susceptabilities to flushing causedby exposure to MMF. Thus, at identical MMF exposures, certain patientsexhibit no flushing while other patients exhibit flushing. For thisreason, in the present context, a reduction of flushing is intended todenote a decrease in the incidence/frequency among a given treatedpatient population of flushing observed after administration of thecompound(s) according to the disclosures herein. The incidence/frequencyof flushing observed after administration of the same compound(s) but atpharmacokinetic parameters (i.e., Cmax and slopes of the MMF bloodplasma concentration versus time curves) exceeding those set forthherein is used as the basis for comparison. The incidence/frequency offlushing in a patient population can be measured, e.g., as described byO'toole et al. Cancer 2000, 88(4), 770-776. Typically, theincidence/frequency of flushing is measured and expressed as thepercentage of patients within a test group who experience flushing.

In the context of treating multiple sclerosis by systemicallyadministering MMF and/or an MMF prodrug, the only reported incidences offlushing reported to date have been in connection with the clinicaltesting of Biogen Idec's BG-12 product, which is a delayed release(i.e., enteric coated microtablets) oral dosage form of the MMF prodrugdimethyl fumarate; see, e.g., Sheikh et al., Safety Tolerability andPharmacokinetics of BG-12 Administered with and without Aspirin, KeyFindings from a Randomized, Double-blind, Placebo-controlled Trial inHealthy Volunteers, Poster P04.136 presented at the 64^(th) AnnualMeeting of the American Academy of Neurology, Apr. 21-28, 2012, NewOrleans, La.; Dawson et al., Bioequivalence of BG-12 (Dimethyl Fumarate)Administered as a Single 240 mg Capsule and Two 120 mg Capsules:Findings from a Randomized, Two-period Crossover Study, Poster P913presented at the 28th Congress of the European Committee for Treatmentand Research in Multiple Sclerosis, Oct. 10-13, 2012, Lyon, France; andWoodworth et al., Pharmacokinetics of Oral BG-12 Alone Compared withBG-12 and Interferon β-1a or Glatiramer Acetate Administered Together,Studied in Health Volunteers, Poster PO4.207 presented at the 62^(nd)Annual Meeting of the American Academy of Neurology, Apr. 10-17, 2010,Toronto, Ontario, Canada. In these publications, Sheikh reportedflushing incidences of 83% and 100% for patients taking BG-12 only, BIDand TID, respectively; Dawson reported flushing incidences of 84% and86% for two different BG-12 dosage forms; and Woodward reported flushingincidences of 50% and 76% in treatment groups receiving BG-12 alone.Thus, the reported incidences of flushing inpatients taking BG-12averages to 80% across multiple patient populations.

In one aspect, in the context of systemic treatment of multiplesclerosis by systemic administration of MMF and/or an MMF prodrug, areduction in flushing according to the methods disclosed herein isconstrued as a flushing incidence of less than 50% of a treated patientpopulation. In another aspect, the incidence of flushing is less than40% of a treated patient population. In another aspect the incidence offlushing is less than 30% of a treated patient population. The reductionof flushing incidence/frequency, as described above, can be monitored ina clinical trial setting.

In the context of treating psoriasis by systemically administering MMFand/or an MMF prodrug, the only reported incidences of flushingpublished to date have been in connection with the clinical testing ofFumapharm's Fumaderm product, which is a delayed release (i.e., entericcoated tablet) oral dosage form of the MMF prodrug dimethyl fumaratetogether with several different salts of monoethyl fumarate. Monoethylfumarate and salts thereof are not MMF prodrugs. Mrowietz et al.(Treatment of Psoriasis with Fumaric Acid Esters: Results of aprospective Multicenter Study, British Journal of Dermatology, 1998,138(3), 456-460) report flushing incidence of 31%. Other reportedflushing incidence in psoriasis patients taking Fumaderm of about 30%and one-third of patients are common.

In one aspect, in the context of systemic treatment of psoriasis bysystemic administration of MMF and/or an MMF prodrug, a reduction influshing according to the methods disclosed herein is construed as aflushing incidence of less than 20% of a treated patient population. Inanother aspect, the incidence of flushing is less than 15% of a treatedpatient population. In another aspect the incidence of flushing is lessthan 10% of a treated patient population. The reduction of flushingincidence/frequency, as described above, can be monitored in a clinicaltrial setting.

In accordance with a first aspect of the presently disclosed treatmentmethods, the MMF and/or MMF prodrug is systemically administered intherapeutic amounts using a dosage form and a dosing frequency thatachieves across a population of patients receiving said treatment amaximum average concentration, as defined herein, of monomethyl fumaratein the blood plasma of the patients of less than 500 ng/ml. In oneembodiment, the maximum average concentration of monomethyl fumarate inthe blood plasma of the patients is less than 400 ng/ml. In anotherembodiment, the maximum average concentration of monomethyl fumarate inthe blood plasma of the patients is less than 350 ng/ml. In yet anotherembodiment, the maximum average concentration of monomethyl fumarate inthe blood plasma of the patients is less than 300 ng/ml. In yet anotherembodiment, the maximum average concentration of monomethyl fumarate inthe blood plasma of the patients is less than 250 ng/ml. In yet anotherembodiment, the maximum average concentration of monomethyl fumarate inthe blood plasma of the patients is less than 200 ng/ml. In yet anotherembodiment, the maximum average concentration of monomethyl fumarate inthe blood plasma of the patients is less than 150 ng/ml. In yet anotherembodiment, the maximum average concentration of monomethyl fumarate inthe blood plasma of the patients is less than 100 ng/ml.

In another aspect, the average Cmax, as defined herein, of monomethylfumarate in the blood plasma of the patients is less than 1100 ng/ml. Incertain aspects, the average Cmax of monomethyl fumarate in the bloodplasma of the patients is maintained at less than 600 ng/ml. In yetanother aspect, the average Cmax of monomethyl fumarate in the bloodplasma of the patients is maintained at less than 500 ng/ml. In yetanother aspect, the average Cmax of monomethyl fumarate in the bloodplasma of the patients is maintained at less than 400 ng/ml. In yetanother aspect, the average Cmax of monomethyl fumarate in the bloodplasma of the patients is maintained at less than 300 ng/ml. In yetanother aspect, the average Cmax of monomethyl fumarate in the bloodplasma of the patients is maintained at less than 200 ng/ml. In yetanother aspect, the average Cmax of monomethyl fumarate in the bloodplasma of the patients is maintained at less than 100 ng/ml.

The following table and FIGS. 13-14 show flushing incidence as afunction of MMF Cmax (maximum average concentration and average Cmax)over patient populations for DMF and an MMF prodrug of Formula (II). Thecurves in the figures were fitted using a Hill E_(max) model.

TABLE 1 Flushing Incidence as a Function of MMF Cmax MMF Mean ofCompound, Dosing Cmax of Individual Formulation*, mg-eq of Frequency/Mean MMF Flushing Dose (mg) and MMF Dose Interval Plot** Cmax***Incidence Source fed or fasted dosed (hrs) (ng/mL) (ng/mL) (%) Dawson⁺DMF, BG-12, 218 BID/12 1250 2340 84 240, fasted Sheikh⁺ DMF, BG-12, 218BID/12 738 1335 83 240, fed Study 1 Compound (1)⁺⁺ 212 BID/12 649 129083 Formulation 1, 400, fasted Study 2 Compound (1), 106 Single Dose 439975 67 Formulation 1, 200, fasted Study 2 Compound (1), 106 Single Dose302 529 58 Formulation 1, 200, fasted Study 2 Compound (1), 106 SingleDose 185 366 42 Formulation 1, 200, fed Study 2 Compound (1), 106 SingleDose 139 217 8 Formulation 2, 200, fed Study 2 Compound (1), 106 SingleDose 129 95 8 Formulation 3, 200, fasted Study 2 Compound (1), 106Single Dose 124 143 0 Formulation 2, 200, fasted Study 2 Compound (1),106 Single Dose 93 106 9 Formulation 4, 200, fed Study 2 Compound (1),106 Single Dose 63 80 8 Formulation 3, 200, fed Study 2 Compound (1),106 Single Dose 50 64 17 Formulation 4, 200, fast *Formulation 2 is thedosage form described in Example 10; Formulation 3 is the dosage formdescribed in Example 3; Formulation 4 is the dosage form described inExample 5; **maximum average Concentration; ***average Cmax; ⁺Poster(see above); ⁺⁺Compound (1) referred to in the above table is an MMFprodrug of Formula (II); (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate having the following chemical structure:

The fifth column of the above table lists the values of MMF Cmax of themean plot (maximum average concentration) in decreasing order. As shownin Table 1, as the mean MMF Cmax (maximum average concentration) dropsfrom 649 to 439 ng/ml, the flushing incidence drops below the ratesreported previously in the literature for the BG-12 DMF product. Thesixth column of the above table lists the corresponding mean ofindividual MMF Cmax (Average Cmax) values. As shown in Table 1, as themean MMF Cmax (Average Cmax) drops below 1100 ng/ml, the flushingincidence drops below the rates reported previously in the literaturefor the BG-12 DMF product.

In accordance with a second aspect of the presently disclosed treatmentmethods, the MMF and/or MMF prodrug is systemically administered intherapeutic amounts using a dosage form and a dosing frequency thatachieves across a population of patients receiving said treatment anaverage maximum rate of rise in MMF concentration in the blood plasma ofthe patients of less than 0.25 wt % ng-eq of MMF dosed/ml/hr. In oneembodiment, the average maximum rate of rise in MMF concentration in theblood plasma of the patients is less than 0.20 wt % ng-eq of MMFdosed/ml/hr. In another embodiment, the average maximum rate of rise inMMF concentration in the blood plasma of the patients is less than 0.15wt % ng-eq of MMF dosed/ml/hr. In yet another embodiment, the averagemaximum rate of rise in MMF concentration in the blood plasma of thepatients is less than 0.10 wt % ng-eq of MMF dosed/ml/hr.

In one embodiment, the methods comprise controlling administration ofthe compound(s) to the patient to achieve across a population ofpatients receiving said controlled administration of compound(s), anaverage maximum rate of rise in monomethyl fumarate concentration in theblood plasma of the patients of less than 0.25 wt % ng-eq of MMFdosed/ml/hr, and an average monomethyl fumarate concentration in theblood plasma of the patients, measured at a time of said maximum rate ofrise, of less than 200 ng/ml. In another embodiment, the average maximumrate of rise in monomethyl fumarate concentration in the blood plasma ofthe patients is less than 0.15 wt % ng-eq of MMF dosed/ml/hr, and anaverage monomethyl fumarate concentration in the blood plasma of thepatients, measured at a time of said maximum rate of rise, is less than180 ng/ml. In yet another embodiment, the average maximum rate of risein monomethyl fumarate concentration in the blood plasma of the patientsis less than 0.10 wt % ng-eq of MMF dosed/ml/hr, and an averagemonomethyl fumarate concentration in the blood plasma of the patients,measured at a time of said maximum rate of rise, is less than 140 ng/ml.

The maximum slope values (% dose and ng) for different dosage treatmentsare given in Table 2. The FIGS. 15-16 show plots of maximum MMF slope vsflushing incidence. The curves in the figures were fitted using a HillE_(max) model.

TABLE 2 Compound, Flushing Formulation*, Dose Max Slope Max slopeIncidence Source (mg), food % dose/mL/h (ng/mL/hr) (%) Dawson DMF,BG-12, 240 0.5005 1084.3 84 mg, fed Sheikh DMF, BG-12, 240 0.2885 625.083 mg, fed Study 1 Compound (1), 0.3689 789.1 83 Compound (1),Formulation 1 400 mg fast Study 1 Compound (1), 0.3128 669.2 67Formulation 1 200 mg fast Study 2 Compound (1), 0.3448 368.9 58Formulation 1 200 mg fast Study 2 Compound (1), 0.0680 72.7 42Formulation 1 200 mg fed Study 2 Compound (1), 0.0647 69.3 8 Formulation2 200 mg fed Study 2 Compound (1), 0.0718 76.8 0 Formulation 2 200 mgfast Study 2 Compound (1), 0.0542 57.9 8 Formulation 3 200 mg fast Study2 Compound (1), 0.0334 35.7 8 Formulation 3 200 mg fed Study 2 Compound(1), 0.0448 47.9 17 Formulation 4 200 mg fast Study 2 Compound (1),0.0787 84.2 9 Formulation 4 200 mg fed *Formulation 2 is the dosage formdescribed in Example 10; Formulation 3 is the dosage form described inExample 3; Formulation 4 is the dosage form described in Example 5.

In order to achieve the pharmacokinetic values of (i) a maximum averageconcentration of monomethyl fumarate in the blood plasma of the patientsof less than 500 ng/ml, and/or (ii) an average maximum rate of rise inMMF concentration in the blood plasma of the patients of less than 0.25wt % ng-eq of MMF dosed/ml/hr, it is necessary to control theintroduction of MMF and/or MMF prodrug into the patients' bloodstream.For systemic oral delivery, this generally means an oral sustainedrelease dosage form. While sustained and delayed-sustained releasedosage forms of MMF prodrugs of Formula I, and most typically sustainedrelease dosage forms of DMF, have been disclosed in the literature forreducing flushing, we have discovered that such dosage forms in factoffer little improvement in reducing patient flushing, either becausethey achieve too high of a maximum average concentration of monomethylfumarate in the blood plasma of the patients, and/or too high of anaverage maximum rate of rise in MMF concentration in the blood plasma ofthe patients. Specifically, Nilsson et al. in US Patent Publication Nos.2012/0034274 and 2012/0034303 disclose oral sustained release and oraldelayed sustained release dosage forms of DMF, the latter dosage formsbeing enteric coated. Although the Nilsson dosage forms purport toreduce the incidence of flushing in patients, they present theirflushing incidence as a percentage of the patients who flush uponadministration of Fumaderm which contains DMF as a primary activeingredient (see Tables II in both Nilsson publications) and at leastsome of the reported reductions in the incidence of flushing (23% and35% reductions compared to Fumaderm) may well be within the range ofexperimental error or variability within small patient populations. Ofthe many dosage forms disclosed in these two publications, the slowestDMF-releasing dosage forms are in Example 2 of US 2012/0034274 andExamples 16 and 23 of US 2012/0034303. The Example 2 dosage form isshown to release: (i) about 90% of the DMF dose over a period of 3hours, (ii) about 43% of the DMF dose in the third hour of in vitrorelease, and (iii) about 65% of the DMF loading over the second andthird hours of in vitro release. The Example 16 dosage form, which isenteric coated and therefore exhibits little to no release during thefirst 2 hours of the in vitro test at low pH conditions, is shown torelease (i) about 90% of the DMF dose over a period of 3.5 hours markedfrom the start of the near-neutral pH portion of the test, and (ii)about 50-55% of its DMF loading over the second and third hours of invitro release. The Example 23 dosage form is shown to release (i) about90% of the DMF dose over a period of 4 hours, and (ii) about 65% of itsDMF loading over the third and fourth hours of in vitro release. Thus,all of the Nilsson dosage forms release the majority (90%) of their DMFdose in periods of 4 hours or less, measured from the start of DMFrelease.

In contrast to the Nilsson et al. dosage forms, the dosage formsdisclosed herein release MMF and/or MMF prodrug at a slower rate andover longer time periods than the Nilsson dosage forms. The oral dosageforms disclosed herein can be characterized as either enteric-coated,and therefore not designed to release much of the compound in the low pHenvironment of a patient's stomach, or non-enteric coated, in whichrelease of compound in the stomach is not necessarily prohibited.

Thus, for oral enteric-coated dosage forms disclosed herein, the dosageforms contain a therapeutically effective dose of the MMF and/or MMFprodrug and are designed to be administered to each patient in apopulation of patients at a dosing frequency of not more than twice perday. The dosage forms, when subjected to the in vitro dissolution testemploying pH 1.2 for the first 2 hours, and pH 6.8 thereafter, releasesthe dose of MMF and/or MMF prodrug as follows: (i) less than 10 wt % ofthe dose over the first 2 hours of the in vitro dissolution test; (ii)at least 90 wt % of the dose over not less than the first 8 hours of thein vitro dissolution test; (iii) no more than 30 wt % of the dose in anyone hour during the in vitro dissolution test; and (iv) no more than 40wt % of the dose in any consecutive two hours during the in vitrodissolution test.

For oral non-enteric-coated dosage forms disclosed herein, the dosageforms contain a therapeutically effective dose of the MMF and/or MMFprodrug and are designed to be administered to each patient in apopulation of patients at a dosing frequency of not more than twice perday. The dosage forms, when subjected to the in vitro dissolution testemploying pH 1.2 for the first 2 hours, and pH 6.8 thereafter, releasesthe dose of MMF and/or MMF prodrug as follows: (i) at least 90 wt % ofthe dose over not less than the first 8 hours of the in vitrodissolution test; (ii) no more than 30 wt % of the dose in any one hourduring the in vitro dissolution test; and (iii) no more than 40 wt % ofthe dose in any consecutive two hours during the in vitro dissolutiontest.

Suitable sustained release oral dosage forms that achieve the abovedescribed in vitro release profiles are disclosed in Examples 1 and 3(enteric-coated sustained release tablets), 5 (enteric-coated pellets ina Vcaps plus capsule) and 8-15 (non-enteric-coated, compression coatedtablets) herein.

Compounds

Certain embodiments of the methods disclosed herein utilize a compoundof Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ is chosen froma C₁ to C₆ alkyl.

In certain embodiments, R¹ is C₂ to C₆ alkyl.

In certain embodiments, R¹ is methyl.

In certain embodiments, R¹ is ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl, pentyl-2-yl, 2-methylbutyl, isopentyl,3-methylbutan-2-yl, neopentyl, tert-pentyl, n-hexyl, hexan-2-yl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3-methylpentan-2-yl,4-methylpentan-2-yl, 2,3-dimethylbutyl, or 3,3-dimethylbutyl.

Examples of compounds of Formula (I) include dimethylfumarate,diethylfumarate, dipropylfumarate, dibutylfumarate, dipentylfumarate,methyl-ethylfumarate, methyl-propylfumarate, methyl-butylfumarate,methyl-pentylfumarate, monoethylfumarate, monopropylfumarate,monobutylfumarate and monopentylfumarate, and/or pharmaceuticallyacceptable salts of any of the foregoing. In certain embodiments, thecompounds of Formula (I) include dimethyl fumarate, methyl ethylfumarate, methyl n-propyl fumarate and methyl i-propyl fumarate,including pharmaceutically acceptable salts thereof. Pharmaceuticallyacceptable salts thereof comprise metal salts, such as a salt selectedfrom alkali metal salts and alkaline earth metal salts including sodium,potassium, calcium, magnesium, strontium or zinc salts, amino acid saltsetc.

Certain embodiments of the methods disclosed herein utilize a compoundof Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R² and R³ are independently chosen from hydrogen, C₁₋₆ alkyl, andsubstituted C₁₋₆ alkyl;

R⁴ and R⁵ are independently chosen from hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, substituted C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, substituted C₁₋₆ alkoxycarbonyl, C₁₋₆ heteroalkyl,substituted C₁₋₆ heteroalkyl, C₄₋₁₂ cycloalkylalkyl, substituted C₄₋₁₂cycloalkylalkyl, C₇₋₁₂ arylalkyl, and substituted C₇₋₁₂ arylalkyl; or R⁴and R⁵ together with the nitrogen to which they are bonded form a ringchosen from a C₅₋₁₀ heteroaryl, substituted C₅₋₁₀ heteroaryl, C₅₋₁₀heterocycloalkyl, and substituted C₅₋₁₀ heterocycloalkyl; and

wherein each substituent group is independently chosen from halogen,—OH, —CN, —CF₃, ═O, —NO₂, benzyl, —C(O)NR¹¹ ₂, —R¹¹, —OR¹¹, —C(O)R¹¹,—COOR¹¹, and —NR¹¹ ₂ wherein each R¹¹ is independently chosen fromhydrogen and C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (II), each substituentgroup is independently chosen from halogen, —OH, —CN, —CF₃, —R¹¹, —OR¹¹,and —NR¹¹ ₂ wherein each R¹¹ is independently chosen from hydrogen andC₁₋₄ alkyl. In certain embodiments, each substituent group isindependently chosen from —OH, and —COOH.

In certain embodiments of a compound of Formula (II), each substituentgroup is independently chosen from ═O, C₁₋₄ alkyl, and —COOR¹¹ whereinR¹¹ is chosen from hydrogen and C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (II), each of R² and R³is hydrogen.

In certain embodiments of a compound of Formula (II), one of R² and R³is hydrogen and the other of R² and R³ is C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (II), one of R² and R³is hydrogen and the other of R² and R³ is chosen from methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

In certain embodiments of a compound of Formula (II), one of R² and R³is hydrogen and the other of R² and R³ is methyl.

In certain embodiments of a compound of Formula (II), R⁴ and R⁵ areindependently chosen from hydrogen and C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (II), R⁴ and R⁵ areindependently chosen from hydrogen and C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (II), R⁴ and R⁵ areindependently chosen from hydrogen, methyl, and ethyl.

In certain embodiments of a compound of Formula (II), each of R⁴ and R⁵is hydrogen; in certain embodiments, each of R⁴ and R⁵ is methyl; and incertain embodiments, each of R⁴ and R⁵ is ethyl.

In certain embodiments of a compound of Formula (II), R⁴ is hydrogen;and R⁵ is chosen from C₁₋₄ alkyl, substituted C₁₋₄ alkyl wherein thesubstituent group is chosen from ═O, —OR¹¹, —COOR¹¹, and —NR¹¹ ₂,wherein each R¹¹ is independently chosen form hydrogen and C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (II), R⁴ is hydrogen;and R⁵ is chosen from C₁₋₄ alkyl, benzyl, 2-methoxyethyl, carboxymethyl,carboxypropyl, 1,3,4-thiadiazolyl, methoxy, 2-methoxycarbonyl,2-oxo(1,3-oxazolidinyl), 2-(methylethoxy)ethyl, 2-ethoxyethyl,(tert-butyloxycarbonyl)methyl, (ethoxycarbonyl)methyl, carboxymethyl,(methylethyl)oxycarbonylmethyl, and ethoxycarbonylmethyl.

In certain embodiments of a compound of Formula (II), R⁴ and R⁵ togetherwith the nitrogen to which they are bonded form a ring chosen from aC₅₋₆ heterocycloalkyl, substituted C₅₋₆ heterocycloalkyl, C₅₋₆heteroaryl, and substituted C₅₋₆ heteroaryl ring. In certain embodimentsof a compound of Formula (II), R⁴ and R⁵ together with the nitrogen towhich they are bonded form a ring chosen from a C₅ heterocycloalkyl,substituted C₅ heterocycloalkyl, C₅ heteroaryl, and substituted C₅heteroaryl ring. In certain embodiments of a compound of Formula (II),R⁴ and R⁵ together with the nitrogen to which they are bonded form aring chosen from a C₆ heterocycloalkyl, substituted C₆ heterocycloalkyl,C₆ heteroaryl, and substituted C₆ heteroaryl ring. In certainembodiments of a compound of Formula (II), R⁴ and R⁵ together with thenitrogen to which they are bonded form a ring chosen from piperazine,1,3-oxazolidinyl, pyrolidine, and morpholine ring.

In certain embodiments of a compound of Formula (II), one of R² and R³is hydrogen and the other of R² and R³ is C₁₋₆ alkyl; R⁴ is hydrogen;and R⁵ is chosen from hydrogen, C₁₋₆ alkyl, and benzyl.

In certain embodiments of a compound of Formula (II), one of R² and R³is hydrogen and the other of R² and R³ is C₁₋₆ alkyl; R⁴ is methyl; andR⁵ is chosen from hydrogen, C₁₋₆ alkyl, and benzyl.

In certain embodiments of a compound of Formula (II), one of R² and R³is hydrogen and the other of R² and R³ is chosen from hydrogen and C₁₋₆alkyl; and each of R⁴ and R⁵ is C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (II), one of R² and R³is hydrogen and the other of R² and R³ is chosen from hydrogen and C₁₋₆alkyl; and each of R⁴ and R⁵ is C₁₋₆ alkyl. In certain embodiments of acompound of Formula (II), each of R² and R³ is hydrogen; and each of R⁴and R⁵ is C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (II), one of R² and R³is hydrogen and the other of R² and R³ is chosen from hydrogen and C₁₋₄alkyl; R⁴ is hydrogen; and R⁵ is chosen from C₁₋₄ alkyl and substitutedC₁₋₄ alkyl, wherein the substituent group is chosen from ═O, —OR¹¹,—COOR¹¹, and —NR¹¹ ₂, wherein each R¹¹ is independently chosen formhydrogen and C₁₋₄ alkyl. In certain embodiments of a compound of Formula(II), one of R² and R³ is hydrogen and the other of R² and R³ is methyl;R⁴ is hydrogen; and R⁵ is chosen from C₁₋₄ alkyl and substituted C₁₋₄alkyl, wherein the substituent group is chosen from ═O, —OR¹¹, —COOR¹¹,and —NR¹¹ ₂, wherein each R¹¹ is independently chosen form hydrogen andC₁₋₄ alkyl. In certain embodiments of a compound of Formula (II), eachof R² and R³ is hydrogen; R⁴ is hydrogen; and R⁵ is chosen from C₁₋₄alkyl and substituted C₁ alkyl, wherein the substituent group is chosenfrom ═O, —OR¹¹, —COOR¹¹, and —NR¹¹ ₂, wherein each R¹¹ is independentlychosen form hydrogen and C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (II), R⁴ and R⁵ togetherwith the nitrogen to which they are bonded form a C₅₋₁₀ heterocycloalkylring.

In certain embodiments of a compound of Formula (II), one of R² and R³is hydrogen and the other of R² and R³ is chosen from hydrogen and C₁₋₆alkyl; and R⁴ and R⁵ together with the nitrogen to which they are bondedform a ring chosen from a C₅₋₆ heterocycloalkyl, substituted C₅₋₆heterocycloalkyl, C₅₋₆ heteroaryl, and substituted C₅₋₆ heteroaryl ring.In certain embodiments of a compound of Formula (II), one of R² and R³is hydrogen and the other of R² and R³ is methyl; and R⁴ and R⁵ togetherwith the nitrogen to which they are bonded form a ring chosen from aC₅₋₆ heterocycloalkyl, substituted C₅₋₆ heterocycloalkyl, C₅₋₆heteroaryl, and substituted C₅₋₆ heteroaryl ring. In certain embodimentsof a compound of Formula (II), each of R² and R³ is hydrogen; and R⁴ andR⁵ together with the nitrogen to which they are bonded form a ringchosen from a C₅₋₆ heterocycloalkyl, substituted C₅₋₆ heterocycloalkyl,C₅₋₆ heteroaryl, and substituted C₅₋₆ heteroaryl ring.

In certain embodiments of a compound of Formula (II), one of R² and R³is hydrogen and the other of R² and R³ is chosen from hydrogen and C₁₋₆alkyl; and R⁴ and R⁵ together with the nitrogen to which they are bondedform a ring chosen from morpholine, piperazine, and N-substitutedpiperazine.

In certain embodiments of a compound of Formula (II), one of R² and R³is hydrogen and the other of R² and R³ is chosen from hydrogen and C₁₋₆alkyl; and R⁴ and R⁵ together with the nitrogen to which they are bondedform a ring chosen from morpholine, piperazine, and N-substitutedpiperazine.

In certain embodiments of a compound of Formula (II), R² is hydrogen,and in certain embodiments, R³ is hydrogen.

In certain embodiments of a compound of Formula (II), R⁴ and R⁵ areindependently chosen from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl,C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₄₋₁₂ cycloalkylalkyl, substitutedC₄₋₁₂ cycloalkylalkyl, C₇₋₁₂ arylalkyl, substituted C₇₋₁₂ arylalkyl,C₁₋₆ heteroalkyl, substituted C₁₋₆ heteroalkyl, C₆₋₁₀ heteroaryl,substituted C₆₋₁₀ heteroaryl, C₄₋₁₂ heterocycloalkylalkyl, substitutedC₄₋₁₂ heterocycloalkylalkyl, C₇₋₁₂ heteroarylalkyl, substituted C₇₋₁₂heteroarylalkyl; or R⁴ and R⁵ together with the nitrogen to which theyare bonded form a ring chosen from a C₅₋₁₀ heteroaryl, substituted C₅₋₁₀heteroaryl, C₅₋₁₀ heterocycloalkyl, and substituted C₅₋₁₀heterocycloalkyl.

In certain embodiments, the Formula (II) compound is chosen from:

-   (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;-   methyl [N-benzylcarbamoyl]methyl (2E)but-2-ene-1,4-dioate;-   methyl 2-morpholin-4-yl-2-oxoethyl (2E)but-2-ene-1,4-dioate;-   (N-butylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;-   [N-(2-methoxyethyl)carbamoyl]methyl methyl (2E)but-2-ene-1,4-dioate;-   2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}acetic    acid;-   4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic    acid;-   methyl (N-(1,3,4-thiadiazol-2-yl)carbamoyl)methyl    (2E)but-2-ene-1,4-dioate;-   (N,N-dimethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;-   (N-methoxy-N-methylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;-   bis-(2-methoxyethylamino)carbamoyl]methyl methyl    (2E)but-2-ene-1,4-dioate;-   [N-(methoxycarbonyl)carbamoyl]methyl methyl (2E)but-2ene-1,4-dioate;-   4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic    acid, sodium salt;-   methyl 2-oxo-2-piperazinylethyl (2E)but-2-ene-1,4-dioate;-   methyl 2-oxo-2-(2-oxo(1,3-oxazolidin-3-yl)ethyl    (2E)but-2-ene-1,4-dioate;-   {N-[2-(dimethylamino)ethyl]carbamoyl}methyl methyl (2E)but-2-ene-1,4    dioate;-   methyl 2-(4-methylpiperazinyl)-2-oxoethyl (2E)but-2-ene-1,4-dioate;-   methyl {N-[(propylamino)carbonyl]carbamoyl}methyl    (2E)but-2-ene-1,4-dioate;-   2-(4-acetylpiperazinyl)-2-oxoethyl methyl (2E)but-2-ene-1,4-dioate;-   {N,N-bis[2-(methylethoxy)ethyl]carbamoyl}methyl methyl    (2E)but-2-ene-1,4-dioate;-   methyl 2-(4-benzylpiperazinyl)-2-oxoethyl (2E)but-2-ene-1.4-dioate;-   [N,N-bis(2-ethoxyethyl)carbamoyl]methyl methyl    (2E)but-2-ene-1,4-dioate;-   2-{(2S)-2-[(tert-butyl)oxycarbonyl]pyrrolidinyl}-2-oxoethyl methyl    (2E)but-2ene-1,4-dioate;-   1-{2-{(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetyl}(2S)pyrrolidine-2-carboxylic    acid;-   (N-{[tert-butyl)oxycarbonyl]methyl}-N-methylcarbamoyl)methyl methyl    (2E)but-2-ene-1,4-dioate;-   {N-(ethoxycarbonyl)methyl]-N-methylcarbamoyl}methyl methyl    (2E)but-2-ene-1,4-dioate;-   methyl 1-methyl-2-morpholin-4-yl-2-oxoethyl    (2E)but-2-ene-1,4-dioate;-   (1S)-[N,N-bis(2-methoxyethyl)carbamoyl]ethyl methyl    (2E)but-2-ene-1,4-dioate;-   (1S)-(N,N-dimethylcarbamoyl)ethyl methyl (2E)but-2-ene-1,4-dioate;-   2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxyl]-N-methylacetylamino}acetic    acid;-   (N-{[(tert-butyl)oxycarbonyl]methyl}carbamoyl)methyl methyl    (2E)but-2-ene-1,4-dioate;-   methyl    (N-methyl-N-{[(methylethyl)oxycarbonyl]methyl}carbamoyl)methyl    (2E)but-2-ene-1,4-dioate;-   {N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}methyl methyl    (2E)but-2-ene-1,4-dioate;-   1-{N-[(ethoxycarbonyl)methyl]-N-benzylcarbamoyl}ethyl methyl    (2E)but-2-ene-1,4-dioate;-   1-{N-[(ethoxycarbonyl)methyl]-N-methylcarbamoyl}ethyl methyl    (2E)but-2-ene-1,4-dioate;-   (1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl methyl    (2E)but-2-ene-1,4-dioate;-   (1S)-1-[N,N-bis(2-methoxyethyl)carbamoyl]ethyl methyl    (2E)but-2-ene-1,4-dioate;-   (1R)-1-(N,N-diethylcarbamoyl)ethyl methyl (2E)but-2-ene-1,4-dioate;    and-   pharmaceutically acceptable salts of any of the foregoing.

In certain embodiments of a compound of Formula (II), the compound ischosen from:

-   (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;-   methyl [N-benzylcarbamoyl]methyl (2E)but-2-ene-1,4-dioate;-   methyl 2-morpholin-4-yl-2-oxoethyl (2E)but-2-ene-1,4-dioate;-   (N-butylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;-   [N-(2-methoxyethyl)carbamoyl]methyl methyl (2E)but-2-ene-1,4-dioate;-   2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}acetic    acid;-   {2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic    acid;-   Methyl (N-(1,3,4-thiadiazol-2yl)carbamoyl)methyl    (2E)but-2ene-1,4-dioate;-   (N,N-dimethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;-   (N-methoxy-N-methylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate;-   bis-(2-methoxyethylamino)carbamoyl]methyl methyl    (2E)but-2-ene-1,4-dioate;-   [N-(methoxycarbonyl)carbamoyl]methyl methyl (2E)but-2ene-1,4-dioate;-   methyl 2-oxo-2-piperazinylethyl (2E)but-2-ene-1,4-dioate;-   methyl 2-oxo-2-(2-oxo(1,3-oxazolidin-3yl)ethyl    (2E)but-2ene-1,4-dioate;-   {N-[2-(dimethylamino)ethyl]carbamoyl}methyl methyl (2E)but-2ene-1,4    dioate;-   (N-[(methoxycarbonyl)ethyl]carbamoyl)methyl methyl    (2E)but-2-ene-1,4-dioate;-   2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}propanoic    acid; and

pharmaceutically acceptable salts of any of the foregoing.

In certain embodiments of a compound of Formula (II), the compound isselected from (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate:

or a pharmaceutically acceptable salt thereof;

and (methyl 2-morpholin-4-yl-2-oxoethyl (2E)but-2-ene-1,4-dioate:

or a pharmaceutically acceptable salt thereof.

Certain embodiments of the methods disclosed herein utilize a compoundof Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R⁶ is chosen from C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₁₋₆ heteroalkyl,substituted C₁₋₆ heteroalkyl, C₃₋₈ cycloalkyl, substituted C₃₋₈cycloalkyl, C₆₋₈ aryl, substituted C₆₋₈ aryl, and —OR¹⁰ wherein R¹⁰ ischosen from C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,substituted C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, and substituted C₆₋₁₀ aryl;and

R⁷ and R⁸ are independently chosen from hydrogen, C₁₋₆ alkyl, andsubstituted C₁₋₆ alkyl;

wherein each substituent group is independently chosen from halogen,—OH, —CN, —CF₃, ═O, —NO₂, benzyl, —C(O)NR¹¹ ₂, —R¹¹, —OR¹¹, —C(O)R¹¹,—COOR¹¹, N(R¹¹)C(O)C(R¹¹)₂NR¹¹ ₂, and —NR¹¹ ₂ wherein each R¹¹ isindependently chosen from hydrogen and C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (III), each substituentgroup is independently chosen from halogen, —OH, —CN, —CF₃, —R¹¹, —OR¹¹,and —NR¹¹ ₂ wherein each R¹¹ is independently chosen from hydrogen andC₁₋₄ alkyl.

In certain embodiments of a compound of Formula (III), each substituentgroup is independently chosen from ═O, C₁₋₄ alkyl, and —COOR¹¹ whereinR¹¹ is chosen from hydrogen and C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (III), one of R⁷ and R⁸is hydrogen and the other of R⁷ and R⁸ is C₁₋₆ alkyl. In certainembodiments of a compound of Formula (II), one of R⁷ and R⁸ is hydrogenand the other of R⁷ and R⁸ is C₁₋₄ alkyl.

In certain embodiments of a compound of Formula (III), one of R⁷ and R⁸is hydrogen and the other of R⁷ and R⁸ is chosen from methyl, ethyl,n-propyl, and isopropyl. In certain embodiments of a compound of Formula(III), each of R⁷ and R⁸ is hydrogen.

In certain embodiments of a compound of Formula (III), R⁶ is C₁₋₆ alkyl;one of R⁷ and R⁸ is hydrogen and the other of R⁷ and R⁸ is C₁₋₆ alkyl.

In certain embodiments of a compound of Formula (III), R⁶ is —OR¹⁰.

In certain embodiments of a compound of Formula (III), R¹⁰ is chosenfrom C₁₋₄ alkyl, cyclohexyl, and phenyl.

In certain embodiments of a compound of Formula (III), R⁶ is chosen frommethyl, ethyl, n-propyl, and isopropyl; one of R⁷ and R⁸ is hydrogen andthe other of R⁷ and R⁸ is chosen from methyl, ethyl, n-propyl, andisopropyl.

In certain embodiments of a compound of Formula (III), R⁶ is substitutedC₁₋₂ alkyl, wherein each of the one or more substituent groups arechosen from —COOH, —NHC(O)CH₂NH₂, and —NH₂.

In certain embodiments of a compound of Formula (III), R⁶ is chosen fromethoxy, methylethoxy, isopropyl, phenyl, cyclohexyl, cyclohexyloxy,—CH(NH₂)CH₂COOH, —CH₂CH(NH₂)COOH, —CH(NHC(O)CH₂NH₂)—CH₂COOH, and—CH₂CH(NHC(O)CH₂NH₂)—COOH.

In certain embodiments of a compound of Formula (III), one of R⁷ and R⁸is hydrogen and the other of R⁷ and R⁸ is chosen from hydrogen, methyl,ethyl, n-propyl, and isopropyl; and R⁶ is chosen from C₁₋₃ alkyl andsubstituted C₁₋₃ alkyl, wherein each of the one or more substituentgroups are chosen from —COOH, —NHC(O)CH₂NH₂, and —NH₂, —OR¹⁰ wherein R¹⁰is chosen from C₁₋₃ alkyl and cyclohexyl, phenyl, and cyclohexyl.

In certain embodiments of a compound of Formula (III), the compound ischosen from:

-   [1-(ethoxycarbonyloxy)]ethyl methyl (2E)but-2-ene-1,4-dioate;-   methyl [1-(methylethoxycarbonyloxy)]ethyl (2E)but-2-ene-1,4-dioate;-   [1-(cyclohexyloxycarbonyloxy)]ethyl methyl (2E)but-2-ene-1,4-dioate;    and

pharmaceutically acceptable salts of any of the foregoing.

In certain embodiments of a compound of Formula (III), the compound ischosen from:

-   methyl (2-methylpropanoyloxy)ethyl (2E)but-2-ene-1,4-dioate;-   methyl [1-(phenylcarbonyloxy)]ethyl (2E)but-2-ene-1,4-dioate;-   [1-(cyclohexylcarbonyloxy)]butyl methyl (2E)but-2-ene-1,4-dioate;-   1-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethyl methyl    (2E)but-2-ene-1,4-dioate;-   methyl 2-methyl-1-phenylcarbonyloxypropyl (2E)but-2-ene-1,4-dioate;    and

pharmaceutically acceptable salts of any of the foregoing.

In certain embodiments of a compound of Formula (III), the compound ischosen from:

-   [1-(ethoxycarbonyloxy)]ethyl methyl (2E)but-2-ene-1,4-dioate;-   methyl [1-(methylethoxycarbonyloxy)]ethyl (2E)but-2-ene-1,4-dioate;-   methyl [1-(2-methylpropanoyloxy)]ethyl (2E)but-2-ene-1,4-dioate;-   methyl[1-phenylcarbonyloxy]ethyl (2E)but-2-ene-1,4-dioate;-   [1-cyclohexylcarbonyloxy]butyl methyl (2E)but-2-ene-1,4-dioate;-   [(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethyl methyl    (2E)but-2-ene-1,4-dioate;-   [1-(cyclohexyloxycarbonyloxy)]ethyl methyl (2E)but-2-ene-1,4-dioate;    methyl 2-methyl-1-phenylcarbonyloxypropyl (2E)but-2-ene-1,4-dioate;-   3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-aminopropanoic    acid;-   3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-aminopropanoic    acid;-   3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-(2-aminoacetylamino)propanoic    acid;-   3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-(2-aminoacetylamino)propanoic    acid;

and

pharmaceutically acceptable salts of any of the foregoing.

In certain embodiments of a compound of Formula (III), the compound ischosen from:

-   3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-aminopropanoic    acid, 2,2,2-trifluoroacetic acid salt;-   3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-aminopropanoic    acid, 2,2,2-trifluoroacetic acid salt;-   3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-(2-aminoacetylamino)propanoic    acid, 2,2,2-trifluoroacetic acid salt;-   3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-(2-aminoacetylamino)propanoic    acid, 2,2,2-trifluoroacetic acid salt;-   3-{{1-{[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]}ethoxycarbonyl}}(2S)-2-aminopropanoic    acid, hydrochloride salt; and

pharmaceutically acceptable salts of any of the foregoing.

Certain embodiments of the methods disclosed herein utilize a compoundof Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein n is an integerfrom 2 to 6.

In certain embodiments of a compound of Formula (IV), n is 2, n is 3, nis 4, n is 5, and in certain embodiments, n is 6.

In certain embodiments of a compound of Formula (IV), the compound is apharmaceutically acceptable salt.

In certain embodiments of a compound of Formula (IV), the compound isthe hydrochloride salt.

Synthesis of Compounds

MMF can be synthesized according to the methods described in Dymicky,Preparation of Monomethyl Fumarate, Organic Preparations and ProceduresInternational: The New Journal for Organic Synthesis, Vol 14, Issue 4,1983; and Spatz et al., J. Org. Chem., 1958, 23 (10), 1559-1560.

DMF can be synthesized according to the methods described in ChinesePatent Publication CN 101318901A, the disclosures of which areincorporated herein by reference.

Compounds of Formula (I) can be synthesized according to the methodsdescribed in Speiser et al., U.S. Pat. No. 5,424,332, at column 3, line33 through column 4, line 2, the disclosures of which are incorporatedherein by reference.

Compounds of Formula (II) can be synthesized according to the methodsdescribed in Gangakhedkar et al., U.S. Pat. No. 8,148,414, at column 23,line 44 through column 26, line 55 and column 28, line 10 through column29, line 34, the disclosures of which are incorporated herein byreference.

Compounds of Formula (III) can be synthesized according to the methodsdescribed in Gangakhedkar et al., U.S. Pat. No. 8,148,414, at column 29,line 43 through column 31, line 13, the disclosures of which areincorporated herein by reference.

Compounds of Formula (IV) can be synthesized according to the methodsdescribed in Cundy et al., U.S. patent application Ser. No. 13/761,864,filed Feb. 7, 2013, at page 34, line 21 through page 41, line 3, thedisclosures of which are incorporated herein by reference.

Pharmaceutical Compositions

Pharmaceutical compositions provided by the present disclosure maycomprise a therapeutically effective amount of MMF and/or a prodrug ofMMF together with a suitable amount of one or more pharmaceuticallyacceptable vehicles so as to provide a composition for properadministration to a patient. Suitable pharmaceutical vehicles aredescribed in the art.

In certain embodiments, MMF and/or a compound of Formulae (I)-(IV) maybe incorporated into pharmaceutical compositions to be administeredorally. Oral administration of such pharmaceutical compositions mayresult in uptake of MMF and/or a compound of Formulae (I)-(IV)throughout the intestine and entry into the systemic circulation. Suchoral compositions may be prepared in a manner known in thepharmaceutical art and comprise MMF and/or a compound of Formulae(I)-(IV) and at least one pharmaceutically acceptable vehicle. Oralpharmaceutical compositions may include a therapeutically effectiveamount of MMF and/or a compound of Formulae (I)-(IV) and a suitableamount of a pharmaceutically acceptable vehicle, so as to provide anappropriate form for administration to a patient.

MMF and/or a compound of Formulae (I)-(IV) may be incorporated intopharmaceutical compositions to be administered by any other appropriateroute of systemic administration including intramuscular, intravenousand oral.

Pharmaceutical compositions comprising MMF and/or a compound of Formulae(I)-(IV) and may be manufactured by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, or lyophilizing processes. Pharmaceuticalcompositions may be formulated in a conventional manner using one ormore physiologically acceptable carriers, diluents, excipients, orauxiliaries, which facilitate processing of MMF and/or a compound ofFormulae (I)-(IV) or crystalline forms thereof and one or morepharmaceutically acceptable vehicles into formulations that can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Pharmaceutical compositions provided by thepresent disclosure take the form of sustained-release formulationssuitable for administration to a patient.

Pharmaceutical compositions provided by the present disclosure may beformulated in a unit dosage form. A unit dosage form refers to aphysically discrete unit suitable as a unitary dose for patientsundergoing treatment, with each unit containing a predetermined quantityof MMF and/or a compound of Formulae (I)-(IV) calculated to produce anintended therapeutic effect. A unit dosage form may be for a singledaily dose, for administration 2 times per day, or one of multiple dailydoses, e.g., 3 or more times per day. When multiple daily doses areused, a unit dosage form may be the same or different for each dose. Oneor more dosage forms may comprise a dose, which may be administered to apatient at a single point in time or during a time interval.

In certain embodiments, an oral dosage form provided by the presentdisclosure may be a controlled release dosage form. Controlled deliverytechnologies can improve the absorption of a drug in a particular regionor regions of the gastrointestinal tract. Controlled drug deliverysystems may be designed to deliver a drug in such a way that the druglevel is maintained within a therapeutically effective window andeffective and safe blood levels are maintained for a period as long asthe system continues to deliver the drug with a particular releaseprofile in the gastrointestinal tract. Controlled drug delivery mayproduce substantially constant blood levels of a drug over a period oftime as compared to fluctuations observed with immediate release dosageforms. For some drugs, maintaining a constant blood and tissueconcentration throughout the course of therapy is the most desirablemode of treatment. Immediate release of drugs may cause blood levels topeak above the level required to elicit a desired response, which maywaste the drug and may cause or exacerbate toxic side effects.Controlled drug delivery can result in optimum therapy, and not only canreduce the frequency of dosing, but may also reduce the severity of sideeffects. Examples of controlled release dosage forms include dissolutioncontrolled systems, diffusion controlled systems, ion exchange resins,osmotically controlled systems, erodable matrix systems, pH independentformulations, gastric retention systems, and the like.

An appropriate oral dosage form for a particular pharmaceuticalcomposition provided by the present disclosure may depend, at least inpart, on the gastrointestinal absorption properties of MMF and/or acompound of Formulae (I)-(IV) the stability of MMF and/or a compound ofFormulae (I)-(IV) in the gastrointestinal tract, the pharmacokinetics ofMMF and/or a compound of Formulae (I)-(IV) and the intended therapeuticprofile. An appropriate controlled release oral dosage form may beselected for a particular compound. For example, gastric retention oraldosage forms may be appropriate for compounds absorbed primarily fromthe upper gastrointestinal tract, and sustained release oral dosageforms may be appropriate for compounds absorbed primarily from the lowergastrointestinal tract. Certain compounds are absorbed primarily fromthe small intestine. In general, compounds traverse the length of thesmall intestine in about 3 to 5 hours. For compounds that are not easilyabsorbed by the small intestine or that do not dissolve readily, thewindow for active agent absorption in the small intestine may be tooshort to provide a desired therapeutic effect.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may be practiced with dosage forms adapted to providesustained release of MMF and/or a compound of Formulae (I)-(IV) uponoral administration. Sustained release oral dosage forms may be used torelease drugs over a prolonged time period and are useful when it isdesired that a drug or drug form be delivered to the lowergastrointestinal tract, including the colon. Sustained release oraldosage forms include any oral dosage form that maintains therapeuticconcentrations of a drug in a biological fluid such as the plasma,blood, cerebrospinal fluid, or in a tissue or organ for a prolonged timeperiod. Sustained release oral dosage forms include diffusion-controlledsystems such as reservoir devices and matrix devices,dissolution-controlled systems, osmotic systems, and erosion-controlledsystems. Sustained release oral dosage forms and methods of preparingthe same are well known in the art.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any systemic dosage form of the MMFand/or a prodrug of MMF, and wherein, when administered to a patient,the maximum average concentration of MMF in the blood plasma of thepatient is less than 500 ng/ml. In one embodiment, the maximum averageconcentration is less than 400 ng/ml. In another embodiment, the maximumaverage concentration is less than 350 ng/ml. In another embodiment, themaximum average concentration is less than 300 ng/ml. In anotherembodiment, the maximum average concentration is less than 250 ng/ml. Inanother embodiment, the maximum average concentration is less than 200ng/ml. In another embodiment, the maximum average concentration is lessthan 150 ng/ml. In some embodiments, the prodrug of MMF is a compound ofFormulae (I)-(IV).

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any systemic dosage form of the MMFand/or a prodrug of MMF, and wherein, when administered to a patient,the average maximum rate of rise in MMF concentration in the bloodplasma of the patients is less than 0.25 wt % ng-eq of MMF dosed/ml/hr.In one embodiment, the average maximum rate of rise is less than 0.20 wt% ng-eq of MMF dosed/ml/hr. In one embodiment, the average maximum rateof rise is less than 0.15 wt % ng-eq of MMF dosed/ml/hr. In oneembodiment, the average maximum rate of rise is less than 0.10 wt %ng-eq of MMF dosed/ml/hr.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any systemic dosage form of the MMFand/or a prodrug of MMF, and wherein, when administered to a patient,the average maximum rate of rise in MMF concentration in the bloodplasma of the patients is less than 0.25 wt % ng-eq of MMF dosed/ml/hr;and an average MMF concentration in the blood plasma of the patients,measured at a time of said maximum rate of rise, is less than 200 ng/ml.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any systemic dosage form of the MMFand/or a prodrug of MMF, and wherein, when administered to a patient,the average maximum rate of rise in MMF concentration in the bloodplasma of the patients is less than 0.20 wt % ng-eq of MMF dosed/ml/hr;and an average MMF concentration in the blood plasma of the patients,measured at a time of said maximum rate of rise, is less than 200 ng/mlor less than 150 ng/ml.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any systemic dosage form of the MMFand/or a prodrug of MMF, and wherein, when administered to a patient,the average maximum rate of rise in MMF concentration in the bloodplasma of the patients is less than 0.15 wt % ng-eq of MMF dosed/ml/hr;and an average MMF concentration in the blood plasma of the patients,measured at a time of said maximum rate of rise, is less than 180 ng/ml.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any systemic dosage form of the MMFand/or a prodrug of MMF, and wherein, when administered to a patient,the average maximum rate of rise in MMF concentration in the bloodplasma of the patients is less than 0.10 wt % ng-eq of MMF dosed/ml/hr;and an average MMF concentration in the blood plasma of the patients,measured at a time of said maximum rate of rise, is less than 140 ng/ml.

In another embodiment, the prodrug of MMF is a compound of Formulae(I)-(IV).

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any enteric-coated sustained release oraldosage form of the MMF and/or a prodrug of MMF, and wherein, whensubjected to an in vitro dissolution test employing as a dissolutionmedium 750 mL of 0.1 N hydrochloric acid, at pH 1.2, for a period of 2hours, followed by addition of 250 mL of 200 mM tribasic sodiumphosphate buffer resulting in an adjustment of the pH of the dissolutionmedium to 6.8, the dissolution medium being maintained at 37° C. andstirred at 100 rpm, the dosage form releases:

-   -   (i) less than 10 wt % of the dose over an initial 2 hours of the        in vitro dissolution test; (ii) at least 90 wt % of the dose        over not less than an initial 8 hours of the in vitro        dissolution test; (iii) no more than 30 wt % of the dose in any        one hour during the in vitro dissolution test; and (iv) no more        than 40 wt % of the dose in any consecutive two hours during the        in vitro dissolution test.

In one embodiment, the prodrug of MMF is a compound of Formulae(I)-(IV). In another embodiment, the enteric-coated oral dosage form isadministered to a patient at a dosing frequency of not more than twiceper day.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any non-enteric-coated sustained releaseoral dosage form of the MMF and/or a prodrug of MMF, and wherein, whensubjected to an in vitro dissolution test employing as a dissolutionmedium 750 mL of 0.1 N hydrochloric acid, at pH 1.2, for a period of 2hours, followed by addition of 250 mL of 200 mM tribasic sodiumphosphate buffer resulting in an adjustment of the pH of the dissolutionmedium to 6.8, the dissolution medium being maintained at 37° C. andstirred at 100 rpm, the dosage form releases:

-   -   (i) at least 90 wt % of the dose over not less than an initial 8        hours of the in vitro dissolution test;    -   (ii) no more than 30 wt % of the dose in any one hour during the        in vitro dissolution test; and    -   (iii) no more than 40 wt % of the dose in any consecutive two        hours during the in vitro dissolution test.

In one embodiment, the prodrug of MMF is a compound of Formulae(I)-(IV). In another embodiment, the non-enteric-coated oral dosage formis administered to a patient at a dosing frequency of not more thantwice per day.

In certain embodiments, pharmaceutical compositions provided by thepresent disclosure may include any suitable dosage forms that achievethe above described in vitro release profiles. Such dosage forms may beany systemic dosage forms, including sustained release enteric-coatedoral dosage form and sustained release non-enteric-coated oral dosageform. Examples of suitable dosage forms are described herein. Thoseskilled in the formulation art can develop any number of acceptabledosage forms given the dosage forms described in the examples as astarting point.

An appropriate dose of MMF and/or a compound of Formulae (I)-(IV) orpharmaceutical composition comprising MMF and/or a compound of Formulae(I)-(IV) may be determined according to any one of severalwell-established protocols. For example, animal studies such as studiesusing mice, rats, dogs, and/or monkeys may be used to determine anappropriate dose of a pharmaceutical compound. Results from animalstudies may be extrapolated to determine doses for use in other species,such as for example, humans.

Uses

Compounds of Formulae (I)-(IV) are prodrugs of MMF. Thus, compounds ofFormulae (I)-(IV) and pharmaceutical compositions thereof may beadministered to a patient suffering from diseases, disorders,conditions, and symptoms of any of the foregoing for which alkylhydrogen fumarates, such as MMF, are known to provide or are later foundto provide therapeutic benefit. MMF and/or a compound of Formulae(I)-(IV) can be used to treat a disease chosen from adrenalleukodystrophy, AGE-induced genome damage, Alexanders Disease, Alper'sDisease, Alzheimer's disease, amyotrophic lateral sclerosis, anginapectoris, arthritis, asthma, balo concentric sclerosis, Canavan disease,cardiac insufficiency including left ventricular insufficiency, centralnervous system vasculitis, Charcott-Marie-Tooth Disease, childhoodataxia with central nervous system hypomyelination, chronic idiopathicperipheral neuropathy, chronic obstructive pulmonary disease, Crohn'sdisease, diabetic retinopathy, graft versus host disease, hepatitis Cviral infection, herpes simplex viral infection, human immunodeficiencyviral infection, Huntington's disease, irritable bowel disorder,ischemia, Krabbe Disease, lichen planus, macular degeneration,mitochondrial encephalomyopathy, monomelic amyotrophy, multiplesclerosis, myocardial infarction, neurodegeneration with brain ironaccumulation, neuromyelitis optica, neurosarcoidosis, NF-κB mediateddiseases, optic neuritis, pareneoplastic syndromes, Parkinson's disease,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, psoriasis, reperfusion injury, retinopathiapigmentosa, Schilders Disease, subacute necrotizing myelopathy, susacsyndrome, transplantation rejection, transverse myelitis, a tumor,ulcerative colitis, Zellweger's syndrome, granulomas includingannulaire, pemphigus, bollus pemphigoid, behcet's, contact dermatitis,acute dermatitis, chronic dermatitis, alopecia areata (totalis anduniversalis), sarcoidosis, cutaneous sarcoidosis, pyoderma gangrenosum,cutaneous lupus, Crohn's disease or cutaneous Crohn's disease.

Methods of treating a disease in a patient provided by the presentdisclosure comprise administering to a patient in need of such treatmenta therapeutically effective amount of MMF and/or a compound of Formulae(I)-(IV). These compounds, and pharmaceutical compositions thereof,provide therapeutic or prophylactic plasma and/or blood concentrationsof MMF following administration to a patient. MMF and/or a compound ofFormulae (I)-(IV) may be administered in an amount and using a dosingschedule as appropriate for treatment of a particular disease. Dailydoses of MMF and/or a compound of Formulae (I)-(IV) may range from about0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 50 mg/kg,from about 1 mg/kg to about 50 mg/kg, and in certain embodiments, fromabout 5 mg/kg to about 25 mg/kg. In certain embodiments, MMF and/or acompound of Formulae (I)-(IV) may be administered at a dose over timefrom about 1 mg to about 5 g per day, from about 10 mg to about 4 g perday, and in certain embodiments from about 20 mg to about 2 g per day.An appropriate dose of MMF and/or a compound of Formulae (I)-(IV) may bedetermined based on several factors, including, for example, the bodyweight and/or condition of the patient being treated, the severity ofthe disease being treated, the incidence and/or severity of sideeffects, the manner of administration, and the judgment of theprescribing physician. Appropriate dose ranges may be determined bymethods known to those skilled in the art.

MMF and the compounds of Formulae (I)-(IV) may be assayed in vitro andin vivo for the desired therapeutic or prophylactic activity prior touse in humans. In vivo assays, for example using appropriate animalmodels, may also be used to determine whether administration of MMFand/or a compound of Formulae (I)-(IV) is therapeutically effective.

In certain embodiments, a therapeutically effective dose of MMF and/or acompound of Formulae (I)-(IV) may provide therapeutic benefit withoutcausing substantial toxicity including adverse side effects. Toxicity ofMMF and/or a compound of Formulae (I)-(IV) and/or metabolites thereofmay be determined using standard pharmaceutical procedures and may beascertained by those skilled in the art. The dose ratio between toxicand therapeutic effect is the therapeutic index. A dose of MMF and/or acompound of Formulae (I)-(IV) may be within a range capable ofestablishing and maintaining a therapeutically effective circulatingplasma and/or blood concentration of MMF and/or a compound of Formulae(I)-(IV) that exhibits little or no toxicity.

MMF and compounds of Formulae (I)-(IV) may be used to treat a diseasechosen from adrenal leukodystrophy, AGE-induced genome damage,Alexanders Disease, Alper's Disease, Alzheimer's disease, amyotrophiclateral sclerosis, angina pectoris, arthritis, asthma, balo concentricsclerosis, Canavan disease, cardiac insufficiency including leftventricular insufficiency, central nervous system vasculitis,Charcott-Marie-Tooth Disease, childhood ataxia with central nervoussystem hypomyelination, chronic idiopathic peripheral neuropathy,chronic obstructive pulmonary disease, Crohn's disease, diabeticretinopathy, graft versus host disease, hepatitis C viral infection,herpes simplex viral infection, human immunodeficiency viral infection,Huntington's disease, irritable bowel disorder, ischemia, KrabbeDisease, lichen planus, macular degeneration, mitochondrialencephalomyopathy, monomelic amyotrophy, multiple sclerosis, myocardialinfarction, neurodegeneration with brain iron accumulation,neuromyelitis optica, neurosarcoidosis, NF-κB mediated diseases, opticneuritis, pareneoplastic syndromes, Parkinson's disease,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, psoriasis, reperfusion injury, retinopathiapigmentosa, Schilders Disease, subacute necrotizing myelopathy, susacsyndrome, transplantation rejection, transverse myelitis, a tumor,ulcerative colitis, Zellweger's syndrome, granulomas includingannulaire, pemphigus, bollus pemphigoid, behcet's, contact dermatitis,acute dermatitis, chronic dermatitis, alopecia areata (totalis anduniversalis), sarcoidosis, cutaneous sarcoidosis, pyoderma gangrenosum,cutaneous lupus, Crohn's disease or cutaneous Crohn's disease. Theunderlying etiology of any of the foregoing diseases being treated mayhave a multiplicity of origins. Further, in certain embodiments, atherapeutically effective amount of MMF and/or the compound of Formulae(I)-(IV) may be administered to a patient, such as a human, as apreventative measure against the foregoing diseases and disorders. Thus,a therapeutically effective amount of MMF and/or a compound of Formulae(I)-(IV) may be administered as a preventative measure to a patienthaving a predisposition for and/or history of adrenal leukodystrophy,AGE-induced genome damage, Alexanders Disease, Alper's Disease,Alzheimer's disease, amyotrophic lateral sclerosis, angina pectoris,arthritis, asthma, balo concentric sclerosis, Canavan disease, cardiacinsufficiency including left ventricular insufficiency, central nervoussystem vasculitis, Charcott-Marie-Tooth Disease, childhood ataxia withcentral nervous system hypomyelination, chronic idiopathic peripheralneuropathy, chronic obstructive pulmonary disease, Crohn's disease,diabetic retinopathy, graft versus host disease, hepatitis C viralinfection, herpes simplex viral infection, human immunodeficiency viralinfection, Huntington's disease, irritable bowel disorder, ischemia,Krabbe Disease, lichen planus, macular degeneration, mitochondrialencephalomyopathy, monomelic amyotrophy, multiple sclerosis, myocardialinfarction, neurodegeneration with brain iron accumulation,neuromyelitis optica, neurosarcoidosis, NF-κB mediated diseases, opticneuritis, pareneoplastic syndromes, Parkinson's disease,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, psoriasis, reperfusion injury, retinopathiapigmentosa, Schilders Disease, subacute necrotizing myelopathy, susacsyndrome, transplantation rejection, transverse myelitis, a tumor,ulcerative colitis, Zellweger's syndrome, granulomas includingannulaire, pemphigus, bollus pemphigoid, behcet's, contact dermatitis,acute dermatitis, chronic dermatitis, alopecia areata (totalis anduniversalis), sarcoidosis, cutaneous sarcoidosis, pyoderma gangrenosum,cutaneous lupus, Crohn's disease and/or cutaneous Crohn's disease.

Administration

MMF and/or a prodrug of MMF and pharmaceutical compositions thereof maybe administered orally or by any other appropriate route suitable forsystemic, as opposed to local, administration. For example, systemicadministration can be by infusion or bolus injection, by absorptionthrough epithelial or mucocutaneous linings (e.g., oral mucosa, rectal,and intestinal mucosa, etc.). Other suitable routes of systemicadministration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual and inhalation.

The amount of MMF and/or a prodrug of MMF that will be effective in thetreatment of a disease in a patient will depend, in part, on the natureof the condition and can be determined by standard clinical techniquesknown in the art. In addition, in vitro or in vivo assays may beemployed to help identify optimal dosage ranges. A therapeuticallyeffective amount of MMF and/or a prodrug of MMF to be administered mayalso depend on, among other factors, the subject being treated, theweight of the subject, the severity of the disease, the manner ofadministration, and the judgment of the prescribing physician. In thecase of an MMF prodrug, for which MMF is the pharmacologically activemetabolite, the amount of prodrug to be administered is generallydetermined by calculating the weight of any pharmacologically inactivepromoiety that is cleaved during metabolism of the prodrug and thenadministering a MMF equivalent amount of the prodrug.

For systemic administration, a therapeutically effective dose may beestimated initially from in vitro assays. For example, a dose may beformulated in animal models to achieve a beneficial circulatingcomposition concentration range. Initial doses may also be estimatedfrom in vivo data, e.g., animal models, using techniques that are knownin the art. Such information may be used to more accurately determineuseful doses in humans. One having ordinary skill in the art mayoptimize administration to humans based on animal data.

A dose may be administered in a single dosage form or in multiple dosageforms. When multiple dosage forms are used the amount of compoundcontained within each dosage form may be the same or different. Theamount of MMF and/or a prodrug of MMF contained in a dose may depend onthe route of administration and whether the disease in a patient iseffectively treated by acute, chronic, or a combination of acute andchronic administration.

In certain embodiments an administered dose is less than a toxic dose.Toxicity of the compositions described herein may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., by determining the LD₅₀ (the dose lethal to 50% of thepopulation) or the LD₁₀₀ (the dose lethal to 100% of the population).The dose ratio between toxic and therapeutic effect is the therapeuticindex. In certain embodiments, MMF and/or a prodrug of MMF may exhibit ahigh therapeutic index. The data obtained from these cell culture assaysand animal studies may be used in formulating a dosage range that is nottoxic for use in humans. A dose of MMF and/or a prodrug of MMF providedby the present disclosure may be within a range of circulatingconcentrations in for example the blood, plasma, or central nervoussystem, that include the effective dose and that exhibits little or notoxicity. A dose may vary within this range depending upon the dosageform employed and the route of administration utilized. In certainembodiments, an escalating dose may be administered.

Combination Therapy

Methods provided by the present disclosure further compriseadministering one or more pharmaceutically active compounds in additionto MMF and/or a prodrug of MMF. Such compounds may be provided to treatthe same disease or a different disease than the disease being treatedwith the MMF and/or MMF prodrug.

In certain embodiments, MMF and/or an MMF prodrug may be used incombination with at least one other therapeutic agent. In certainembodiments, MMF and/or a MMF prodrug may be administered to a patienttogether with another compound for treating diseases and conditionsincluding: adrenal leukodystrophy, Alexanders Disease, Alper's Disease,balo concentric sclerosis, Canavan disease, central nervous systemvasculitis, Charcott-Marie-Tooth Disease, childhood ataxia with centralnervous system hypomyelination, diabetic retinopathy, graft versus hostdisease, hepatitis C viral infection, herpes simplex viral infection,human immunodeficiency viral infection, Krabbe Disease, lichen planus,macular degeneration, monomelic amyotrophy, neurodegeneration with brainiron accumulation, neuromyelitis optica, neurosarcoidosis, opticneuritis, pareneoplastic syndromes, Pelizaeus-Merzbacher disease,primary lateral sclerosis, progressive supranuclear palsy, SchildersDisease, subacute necrotizing myelopathy, susac syndrome, transversemyelitis, a tumor and Zellweger's syndrome.

MMF and/or an MMF prodrug and the at least one other therapeutic agentmay act additively or, and in certain embodiments, synergistically. Theat least one additional therapeutic agent may be included in the samedosage form as MMF and/or the MMF prodrug or may be provided in aseparate dosage form. Methods provided by the present disclosure canfurther include, in addition to administering MMF and/or an MMF prodrug,administering one or more therapeutic agents effective for treating thesame or different disease than the disease being treated by MMF and/orthe MMF prodrug. Methods provided by the present disclosure includeadministration of MMF and/or an MMF prodrug and one or more othertherapeutic agents provided that the combined administration does notinhibit the therapeutic efficacy of the MMF and/or the MMF prodrugand/or does not typically produce significant and/or substantial adversecombination effects.

In certain embodiments, dosage forms comprising MMF and/or a prodrug ofMMF may be administered concurrently with the administration of anothertherapeutic agent, which may be part of the same dosage form as, or in adifferent dosage form than that comprising MMF and/or a prodrug of MMF.MMF and/or a prodrug of MMF may be administered prior or subsequent toadministration of another therapeutic agent. In certain embodiments ofcombination therapy, the combination therapy may comprise alternatingbetween administering MMF and/or a prodrug of MMF and a compositioncomprising another therapeutic agent, e.g., to minimize adverse drugeffects associated with a particular drug. When MMF and/or a prodrug ofMMF is administered concurrently with another therapeutic agent thatpotentially may produce an adverse drug effect including, but notlimited to, toxicity, the other therapeutic agent may advantageously beadministered at a dose that falls below the threshold at which theadverse drug reaction is elicited.

In certain embodiments, dosage forms comprising MMF and/or a prodrug ofMMF may be administered with one or more substances to enhance, modulateand/or control release, bioavailability, therapeutic efficacy,therapeutic potency, stability, and the like of MMF and/or a prodrug ofMMF. For example, to enhance the therapeutic efficacy of a MMF and/or aprodrug of MMF, the MMF and/or a prodrug of MMF may be co-administeredwith or a dosage form comprising MMF and/or a prodrug of MMF maycomprise one or more active agents to increase the absorption ordiffusion of MMF and/or a prodrug of MMF from the gastrointestinal tractto the systemic circulation, or to inhibit degradation of the MMF and/ora prodrug of MMF in the blood of a patient. In certain embodiments, MMFand/or a prodrug of MMF may be co-administered with an active agenthaving pharmacological effects that enhance the therapeutic efficacy ofa MMF and/or a prodrug of MMF.

EXAMPLES

The following examples illustrate various aspects of the disclosure. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe scope of the disclosure.

Example 1 Preparation of Sustained Release Dosage Form Enteric Coated,15% HPMC in Core, with Barrier Layer

Delayed sustained release tablets containing an MMF prodrug were madehaving the ingredients shown in Table 3:

TABLE 3 Composition of Enteric Coated Sustained Release Tablet (15% HPMCin Core) Quantity Quantity Component Manufacturer Role (mg/tablet) (%w/w) (N,N- XenoPort (Santa Clara, CA) Drug substance 200.00 66.74Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4- dioate [Compound (1)]Hydroxypropyl Cellulose Ashland (Hopewell, VA) Binder 6.19 2.06 LactoseMonohydrate Foremost (Rothschild, WI) Filler 44.95 15.00 Hypromellose2208 Dow Chemical Sustained release 44.95 15.00 (Midland, MI) agentSilicon Dioxide Cabot (Tuscola, IL) Glidant 0.60 0.20 Magnesium StearateMallinckrodt (St. Louis, MO) Lubricant 3.00 1.00 Total Core 299.69100.00 Opadry 03O19184 Colorcon (West Point, PA) Barrier coat 7.13 2.38Total Barrier 7.13 2.38 Coating Methacrylic Acid Co- Evonik IndustriesEnteric polymer 24.20 8.08 polymer Dispersion (Essen, Germany) TriethylCitrate Vertellus (Greensboro, NC) Plasticizer 1.25 0.42 PlasACRYL™ T20Emerson Resources Anti-tacking 2.41 0.80 (Norristown, PA) agent TotalEnteric 27.87 9.30 Coating Total Tablet 334.69 111.68

The tablets were made according to the following steps. The core tabletswere prepared using a wet granulation process. The granulation wasperformed in two batches at 456 g per batch. Compound (1) andhydroxypropyl cellulose were passed through a conical mill with a 610micron round holed screen. Compound (1) and hydroxypropyl cellulose werethen combined in a Key KG-5 granulator bowl and mixed with wateraddition for approximately 7 minutes. The wet granules were dried in aGlatt GPCG-1 fluid bed dryer at 40° C. The two portions of driedgranules were sized by passing through a conical mill with anapproximately 1300 micron grater type screen. The milled granules wereblended with the hypromellose 2208, silicon dioxide, and lactosemonohydrate for 10 minutes in an 8 quart (7.6 l) V-blender. This blendwas passed through an 850 micron mesh screen. The magnesium stearate waspassed through a 600 micron mesh screen and blended with the additionalcore materials in the V-blender for 5 minutes. Core tablets (299.69 mg)were compressed using a GlobePharma Minipress II rotary tablet presswith 8.6 mm round concave tooling. The core tablets had a final meanhardness of approximately 12 kp. For the coating, an aqueous suspensionwas prepared by mixing with an impeller 63.8 g Opadry 03019184 with770.7 g of purified water. The water contained in the suspension isremoved during the film coating process and therefore not included inthe final formulation in Table 3. The tablets were coated with theaqueous suspension in an O'Hara Technologies Labcoat M coater with a 12″(30.5 cm) diameter perforated pan until the desired weight gain ofbarrier coat was achieved. The coating process occurred at an inlettemperature of approximately 52° C. and an outlet temperature of 36° C.After coating, the tablets were dried for 2 hours at 40° C. An aqueoussuspension was prepared by mixing with an impeller 405.1 g methacrylicacid copolymer dispersion, 6.3 g triethyl citrate, 60.6 g PlasACRYL™ T20with 228.1 g water. The water contained in the methacrylic acidcopolymer dispersion and the PlasACRYL™ T20 is removed during the filmcoating process and therefore not included in the final formulation inTable 3. The tablets were coated with the aqueous suspension in theO'Hara Technologies Labcoat M coater until the desired weight gain ofenteric film was achieved. The coating process occurred at an inlettemperature of approximately 40° C. and an outlet temperature of 30° C.After coating, the tablets were dried for 2 hours at 40° C.

Example 2 In Vitro Dissolution Profile of Example 1 Dosage Form

A two-stage dissolution method was used to determine the in vitrodissolution profile of dosage forms prepared according to Example 1. The2-stage dissolution test was used to better approximate the pHconditions experienced by a dosage form after swallowing by a patient,i.e., low pH of the stomach followed by near neutral pH of theintestines. The dosage forms were first placed into a dissolution vessel(USP, Type I, basket) containing 750 mL of 0.1 N hydrochloric acid (pH1.2). After 2 hours, 250 mL of 200 mM tribasic sodium phosphate wasadded to the vessel resulting in a pH adjustment from 1.2 to 6.8. Thedissolution medium was kept at 37° C. and was agitated at 100 rpm.

For the Example 1 dosage forms, samples of the dissolution medium werewithdrawn after 1 and 2 hours in the low pH stage, and at 0.5, 2, 4, 7,10, and 14 hours following buffer addition. The released amount of theMMF prodrug in the samples was determined by reverse phase HPLC using aC18 column and a 7 minute gradient method according to Table 4 whereMobile Phase A is water/0.1% H₃PO₄ and Mobile Phase B iswater/acetonitrile/H₃PO₄ (10/90/0.1 by volume) with UV detection at 210nm.

TABLE 4 HPLC Gradient Conditions Time (minute) % Mobile Phase A % MobilePhase B 0 85 15 5 35 65 5.5 85 15 7 85 15

As shown in FIG. 1, for dosage forms prepared according to Example 1,drug release is delayed for approximately 2 hours, followed by sustainedrelease reaching >90% at 12 hours.

Example 3 Preparation of Delayed Sustained Release Dosage Form EntericCoated, 15% HPMC in Core, without Barrier Layer

Delayed sustained release tablets containing compound (1) were madehaving the ingredients shown in Table 5:

TABLE 5 Composition of Enteric Coated Sustained Release Tablet (15% HPMCin Core, without Barrier Layer) Quantity Quantity Component ManufacturerRole (mg/tablet) (% w/w) (N,N- XenoPort (Santa Clara, CA) Drug 200.0066.74 Diethylcarbamoyl)methyl substance methyl (2E)but-2-ene- 1,4-dioate[Compound 1] Hydroxypropyl Cellulose Ashland Binder 6.18 2.06 (Hopewell,VA) Lactose Monohydrate Foremost Filler 44.95 15.00 (Rothschild, WI)Hypromellose 2208 Dow Chemical Sustained 44.95 15.00 (Midland, MI)release agent Silicon Dioxide Cabot (Tuscola, IL) Glidant 0.60 0.20Magnesium Stearate Mallinckrodt (St. Lubricant 3.00 1.00 Louis, MO)Total Core 299.68 100.00 Methacrylic Acid Co- Evonik Industries Enteric23.42 7.82 polymer Dispersion (Essen, Germany) polymer Triethyl CitrateVertellus Plasticizer 1.21 0.41 (Greensboro, NC) PlasACRYL™ T20 EmersonAnti-tacking 2.33 0.78 Resources agent (Norristown, PA) Total Coat 27.909.00 Total Tablet 327.59 109.00

The tablets were made according to the following steps. The core tabletswere prepared using a wet granulation process. The granulation wasperformed in two batches at 463.9 g per batch. Compound (1) andhydroxypropyl cellulose were passed through a conical mill with a 610micron round holed screen. Compound (1) and hydroxypropyl cellulose werethen combined in a Key KG-5 granulator bowl and mixed with wateraddition for approximately 10 minutes. The wet granules were dried in aGlatt GPCG-1 fluid bed dryer at 40° C. The two portions of driedgranules were blended with silicon dioxide and sized by passing througha conical mill with an approximately 1300 micron grater type screen. Themilled granules were blended with the hypromellose 2208 and lactosemonohydrate for 10 minutes in an 8 quart (7.6 l) V-blender. This blendwas passed through an 850 micron mesh screen. The magnesium stearate waspassed through a 600 micron mesh screen and blended with the additionalcore materials in the V-blender for 5 minutes. Core tablets (299.68 mg)were compressed using a GlobePharma Minipress II rotary tablet presswith 11/32″ round concave tooling. The core tablets had a final meanhardness of approximately 11 kp. For the coating, an aqueous suspensionwas prepared by mixing with an impeller 578.7 g methacrylic acidcopolymer dispersion, 9.0 g triethyl citrate, 86.5 g PlasACRYL™ T20 with325.8 g water. The water contained in the methacrylic acid copolymerdispersion and the PlasACRYL™ T20 is removed during the film coatingprocess and therefore not included in the final formulation in Table 4.The tablets were coated with the aqueous suspension in the O'HaraTechnologies Labcoat M coater until the desired weight gain of entericfilm was achieved. The coating process occurred at an inlet temperatureof approximately 41° C. and an outlet temperature of 31° C. Aftercoating, the tablets were dried for 2 hours at 40° C.

Example 4 Safety, Tolerability, and Pharmacokinetics of Example 3 DosageForm

A randomized, double-blind crossover, food effect, single-dose study ofthe safety, tolerability, and pharmacokinetics of an oral dosage form of(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate in healthyadult subjects was conducted. Twenty-four healthy adult volunteers(males and females) participated in the study. Twelve of the subjectsreceived a dosage form of Example 3, once in a fed condition and once ina fasted condition, with a two-week washout between treatments. Thefasted dosing was achieved by dosing the subject following an overnightfast while the fed dosing was achieved by dosing the subject afterconsuming a high fat-content breakfast. The tested dosage formscontained 200 mg of (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate (107 mg equivalents of methyl hydrogenfumarate).

Blood samples were collected from all subjects prior to dosing, and at0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 30, 36, 48, 60, 72,84, 96, 108 and 120 hours after dosing. Urine samples were collectedfrom all subjects prior to dosing, and complete urine output wasobtained at the 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96 and96-120 hour intervals after dosing. Blood samples were quenchedimmediately with acetonitrile and frozen. Sample aliquots were preparedfor analysis of (i) methyl hydrogen fumarate, (ii)(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, (iii) N,Ndiethyl-2-hydroxy acetamide and (iv)(2S,3S,4S,5R,6R)-6-[(N,N-diethylcarbamoyl)methoxy]-3,4,5-trihydroxy-2H-3,4,5,6-tetrahydropyran-2-carboxylicacid, the latter two being other potential metabolites of(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, usingsensitive and specific LC/MS/MS methods.

The plasma concentration of MMF following oral dosing of the formulationprepared according to Example 3 to fasted and fed healthy adult patientsis shown in FIG. 2. Table 6 shows the preliminary mean (SD)pharmacokinetic data for (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate [Compound (1)] in fed and fasted patients.

TABLE 6 PK Data for Compound (1) Average C_(max) T_(max) AUC_(inf) NFood (ng/mL) (hr) (ng · hr/mL) 12*/8** Fasted 95* 4.17* 400** (26) (0.84) (166)   12*/5*** Fed 80* 9.92* 377*** (39)  (5.50) (132)   *Cmaxand Tmax measured in all 12 subjects, **based on 8 out of 12 subjectswith a defined terminal phase, ***based on 5 out of 12 subjects with adefined terminal phase

The formulation produced mean (SD) maximum MMF concentrations (averageCmax) of 95 (26) ng/mL fasted and 80 (39) ng/mL fed. MMF AUC was 400(160) ng*h/mL fasted and 377 (132) ng*h/mL fed. The time to peakconcentration (Tmax) was 4.17 (0.84) hr fasted and 9.92 (5.50) hr fed.Promoiety was cleared from blood with a half-life around 3 hours.

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate was welltolerated during the trial. All 12 subjects completed the dosing period.All adverse events were mild. One subject in the(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate fed groupreported flushing more frequently than in the fed placebo group. Nosubjects in the fasted (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate group reported flushing, and no subjects ineither the fed or fasted (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate groups reported feeling hot more than forplacebo. A comparison of these adverse events of the formulation toplacebo is shown in Table 7.

TABLE 7 Comparison of Adverse Events Flushing Feeling Hot Fasted FedFasted Fed Placebo 0 1 0 0 Example 3 1 1 0 0 Formulation

Example 5 Preparation of VCaps Plus Capsule Dosage Form

Size 00 VCaps Plus capsules containing 477 mg of extended-release(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate-containingpellets were manufactured with the formulation shown in Table 8:

TABLE 8 Composition of VCaps Plus Capsule Quantity Quantity ComponentManufacturer Role (mg/tablet) (% w/w) (N,N- Cambridge Drug 200.00 60.00Diethylcarbamoyl) (Germantown, substance methyl methyl WI)(2E)but-2-ene- 1,4-dioate Microcrystalline FMC Filler 133.33 40.00Cellulose (Newark, DE) Total Pellet 333.33 100.00 Core EthylcelluloseAshland Water- 20.56 6.17 (Hopewell VA) insoluble coating agentHydroxypropyl Ashland Water soluble 5.00 1.50 Cellulose (Hopewell VA)coating agent Talc Luzenac Anti-tacking 5.00 1.50 (Houston TX) agentDibutyl sebacate Vertellus Plasticizer 2.78 0.83 (Greensboro, NC) TotalBarrier/ 33.33 10.00 Sustained Release Coating Methacrylic Acid EvonikEnteric 88.55 24.15 Co-polymer (Darmstadt, coating agent DispersionGermany) Triethyl Citrate Vertellus Plasticizer 14.30 3.90 (Greensboro,NC) PlasACRYL T20 Emerson Anti-tacking 7.15 1.95 (Norristown, agent PA)Total Enteric 110.00 30.00 Coating VCaps Plus Size Capsugel Capsule111-125 23.29- 00 Capsule (Puebla, 26.22 Mexico)

The capsules were manufactured according to the following process. Anextrusion/spheronization process was selected for the manufacture of thecore pellets for the capsules. The (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate was first screened then mixed withmicrocrystalline cellulose. This blend was then formed into a wet masswith the addition of aqueous acetate buffer (pH 3.5) and the mass thenextruded through a 1.0 mm screen and the extrudates were spheronized (at1200 rpm for 3 minutes) to form the core pellets. These core pellets arethen classed to retain the pellets within 0.85 mm to 1.4 mm before thenext processing step. The pellets were then coated with the targetamount of the sustained release membrane using a hydroalcoholic mixtureof ethylcellulose and hydroxypropyl cellulose. This coating wasperformed in a Wurster-type coater (product temperature at 30° C. andspray rate at 10 g/minute). The overall coating time was approximately 2hours. The coated pellets were dried further in an oven to remove anyresidual solvent. The dried sustained release film-coated pellets werethen enteric coated to the target amount by aqueous film coating in aWurster-type coater (product temperature at 30° C. and a spray rate at10 g/min). The overall coating time was approximately 2 hours. Thecapsules were then filled with the appropriate amount of pellets toachieve the desired dose strength.

Example 6 In Vitro Dissolution Profile of VCaps Plus Capsule Dosage Form

A two-stage dissolution method was used to determine the in vitrodissolution profile of dosage forms prepared according to Example 5 inorder to mimic the conditions of a dosage form as it transits thegastrointestinal tract. Thus, the dosage forms were first placed into adissolution medium having a pH of 1.2, to mimic the conditions of thestomach, and then placed into a dissolution medium of pH 6.8, to mimicthe conditions of the intestines. The dissolution vessel (USP, Type I,basket) initially contained 750 mL of 0.1 N hydrochloric acid (pH 1.2).After 2 hours of dissolution, 250 mL of 200 mM tribasic sodium phosphatewas added to the vessel resulting in a pH adjustment from 1.2 to 6.8.The dissolution medium was kept at 37° C. and was agitated at 100 rpm.

Samples of the dissolution medium were withdrawn at 1 and 2 hoursfollowing the start of the low pH stage, and at 0.5, 2, 4, 7, 10, and 14hours following start of the near-neutral pH stage. The concentration of(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate in solutionwas determined using reverse phase HPLC using a C18 column and aphosphoric acid/acetonitrile/water isocratic mobile phase withphotodiode detection at 210 nm.

The percent of prodrug released from the Example 5 dosage forms overtime is shown in FIG. 3. These dosage forms showed no prodrug release inthe first 2 hours (acid stage) of testing. Slow prodrug release wasobserved after the dissolution medium pH was adjusted to 6.8. Fullprodrug release was achieved after about 20 hours in pH 6.8.

Example 7 Safety, Tolerability, and Pharmacokinetics of Capsule DosageForm

A randomized, double-blind crossover, food effect, single-dose study ofthe safety, tolerability, and pharmacokinetics of a sustained releaseoral dosage form of (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate in healthy adult subjects was conducted. Twelvehealthy adult volunteers (males and females) participated in the study.All twelve subjects received a dosage form of Example 5, once in a fedcondition and once in a fasted condition, with a two-week washoutbetween treatments. The fasted dosing was achieved by dosing the subjectfollowing an overnight fast while the fed dosing was achieved by dosingthe subject after consuming a high fat-content breakfast. The dosageform contains 200 mg of (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate (107 mg equivalents of methyl hydrogenfumarate).

Blood samples were collected from all subjects prior to dosing, and at0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 30, 36, 48, 60, 72,84, 96, 108 and 120 hours after dosing. Urine samples were collectedfrom all subjects prior to dosing, and complete urine output wasobtained at the 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96 and96-120 hour intervals after dosing. Blood samples were quenchedimmediately with acetonitrile and frozen. Sample aliquots were preparedfor analysis of (i) methyl hydrogen fumarate, (ii)(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, (iii) N,Ndiethyl-2-hydroxy acetamide and (iv)(2S,3S,4S,5R,6R)-6-[(N,N-diethylcarbamoyl)methoxy]-3,4,5-trihydroxy-2H-3,4,5,6-tetrahydropyran-2-carboxylicacid, the latter two being other potential metaboliltes of(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, usingsensitive and specific LC/MS/MS methods.

The plasma concentration of MMF following oral dosing of the formulationprepared according to Example 5 to fasted and fed healthy adult patientsis shown in FIG. 4. Table 9 shows the preliminary mean (SD)pharmacokinetic data for (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate in fed and fasted patients.

TABLE 9 PK Data for Capsule Dosage Form Average C_(max) T_(max)AUC_(inf) N Food (ng/mL) (hr) (ng · hr/mL) 12*/10** Fasted  64* 3.08* 257** (34) (0.79) (116) 12 Fed 106  6.42 398 (37) (1.98) (123) *Cmaxand Tmax measured in all 12 subjects, **based on 10 out of 12 subjectswith a defined terminal phase

The formulation produced mean (SD) maximum MMF concentrations (averageCmax) of 64 (34) ng/mL fasted and 106 (37) ng/mL fed. MMF AUC was 257(116) ng*h/mL fasted and 398 (123) ng*h/mL fed. The time to peakconcentration (Tmax) was 3.08 (0.79) hr fasted and 6.42 (1.98) hr fed.Promoiety was cleared from blood with a half-life around 3 hours.(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate was welltolerated during the trial. All 12 subjects completed the dosing period.All adverse events were mild. Two subjects in the(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate fed groupreported flushing more frequently than in the fed placebo group. Nosubjects in the fasted (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate group reported flushing, and no subjects ineither the fed or fasted (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate groups reported feeling hot more than forplacebo. A comparison of these adverse events of the formulation toplacebo is shown in Table 10.

TABLE 10 Comparison of Adverse Events Flushing Feeling Hot Fasted FedFasted Fed Placebo 0 1 0 0 Example 5 2 0 0 0 Formulation

Example 8 Preparation of Compression Coated Tablet Dosage Form(Non-Enteric Coated, 8% HPMC in Core)

Compression coated tablets containing (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate were made having the ingredients shownin Table 11:

TABLE 11 Composition of CCT Dosage Form (Non-Enteric Coated, 8% HPMC inCore) Quantity Quantity Component Manufacturer Role (mg/tablet) (% w/w)(N,N- XenoPort (Santa Clara, Drug substance 100.00 29.19Diethylcarbamoyl)methyl CA) methyl (2E)but-2-ene-1,4- dioateHydroxypropyl Cellulose Aqualon (Hopewell, Binder 3.12 0.91 VA)Hypromellose 2208 Dow Chemical Sustained Release 9.14 2.67 (100000 mPa ·s) (Midland, MI) Polymer Silicon Dioxide Cabot (Tuscola, IL) Glidant0.23 0.06 Magnesium Stearate Mallinckrodt (St. Louis, Lubricant 1.710.50 MO) Total Core 114.20 33.33 Lactose Hydrate Foremost (Rothschild,Filler 157.60 46.00 WI) Hypromellose 2208 Dow Chemical Sustained Release68.52 20.00 (100 mPa · s) (Midland, MI) Polymer Magnesium StearateMallinckrodt (St. Louis, Lubricant 2.28 0.67 MO) Total Mantle 228.4066.67 Total Tablet 342.60 100.00

The tablets were made according to the following steps. The core tabletswere prepared using a wet granulation process. The granulation batchsize was 680 g. (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate was passed through the Quadro Comil U5 with an813 micron screen at 2000 rpm. Hydroxypropyl cellulose was passedthrough a 600 micron mesh screen. (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate and hydroxypropyl cellulose were granulatedwith purified water using a Diosna P1/6 equipped with a 4 L bowl. Thewet granules were screened through an 1180 micron mesh screen and driedon trays in an oven at 30° C. for 6 hours.

The core blend batch size was 5 g. The dried granules,hydroxypropylmethylcellulose (i.e., hypromellose 2208 having 100000mPa·s viscosity), and the silicon dioxide were then passed through a 600micron mesh screen, combined in a glass jar and blended in a Turbulamixer for 5 minutes. Magnesium stearate was passed through a 250 micronscreen and added to the blend before blending an additional 1.5 minutes.Core tablets (114.2 mg) were compressed using a Carver Press with ¼ inch(6.35 mm) round standard concave tooling at 0.4 metric ton (MT) force.The core tablets had a final hardness of approximately 7.6 kp (˜74Newtons).

The mantle blend was prepared using a direct compression process and abatch size of 10 g. The hypromellose 2208 (100 MPa-s viscosity) andlactose hydrate were passed through a 600 micron mesh screen, combinedin a glass jar and blended in a Turbula mixer for 5 minutes. Magnesiumstearate was passed through a 250 micron screen and added to the blendand blended an additional 1.5 minutes. The mantle blend was then appliedto the core tablets using the Carver Press with ⅜ inch (9.53 mm) roundstandard concave tooling. Half the mantle blend (114.2 mg) was weighedout, added to the die, and tamped slightly to flatten. Then, the coretablet was placed into the die and pressed down gently into the mantleblend. The second half of the mantle blend (114.2 mg) was then added ontop of the core tablet and the mantle was compressed using 1.5 MT force.The final compression coated tablets had a total weight of 342.6 mg witha (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate loadingof 100 mg (29.19%). The tablets had a final hardness around 14.7 kp(˜144 Newtons).

Example 9 Preparation of Compression Coated Tablet Dosage FormNon-Enteric Coated, 30% HPMC in Mantle

Compression coated tablets containing (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate were made having the ingredients shownin Table 12:

TABLE 12 Composition of CCT Dosage Form (Non-Enteric Coated, 30% HPMC inMantle) Quantity Quantity Component Manufacturer Role (mg/tablet) (%w/w) (N,N- XenoPort (Santa Clara, Drug substance 100.00 31.78Diethylcarbamoyl)methyl CA) methyl (2E)but-2-ene-1,4- dioateHydroxypropyl Cellulose Aqualon (Hopewell, Binder 3.12 0.99 VA) SiliconDioxide Cabot (Tuscola, IL) Glidant 0.21 0.06 Magnesium StearateMallinckrodt (St. Louis, Lubricant 1.57 0.50 MO) Total Core 104.90 33.33Lactose Hydrate Foremost (Rothschild, Filler 144.76 46.00 WI)Hypromellose 2208 Dow Chemical Sustained Release 62.94 20.00 (100000 mPa· s) (Midland, MI) Polymer Magnesium Stearate Mallinckrodt (St. Louis,Lubricant 2.10 0.67 MO) Total Mantle 209.80 66.67 Total Tablet 314.70100.00

The tablets were made according to the following steps. The core tabletswere prepared using a wet granulation process. The granulation batchsize was 680 g. (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate was passed through the Quadro Comil U5 with an813 micron screen at 2000 rpm. Hydroxypropyl cellulose was passedthrough a 600 micron mesh screen. (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate and hydroxypropyl cellulose were granulatedwith purified water using a Diosna P1/6 equipped with a 4 L bowl. Thewet granules were screened through an 1180 micron mesh screen and driedon trays in an oven at 30° C. for 6 hours.

The core blend batch size was 5 g. The dried granules and the silicondioxide were then passed through a 600 micron mesh screen, combined in aglass jar and blended in a Turbula mixer for 5 minutes. Magnesiumstearate was passed through a 250 micron screen and added to the blendbefore blending an additional 1.5 minutes. Core tablets (104.9 mg) werecompressed using a Carver Press with ¼ inch (6.35 mm) round standardconcave tooling at 0.4 metric ton (MT) force. The core tablets had afinal hardness of approximately 6.1 kp (˜60 Newtons).

The mantle blend was prepared using a direct compression process and abatch size of 100 g. The hydroxypropylmethylcellulose (i.e.,hypromellose 2208 having 100000 MPa-s viscosity) and lactose hydratewere passed through a 600 micron mesh screen, combined in a 1 quart(0.95 l) V-blender and blended for 10 minutes. Magnesium stearate waspassed through a 250 micron screen and added to the blend and blended anadditional 4 minutes. The mantle blend was then applied to the coretablets using the Carver Press with ⅜ inch (9.53 mm) round standardconcave tooling. Half the mantle blend (104.9 mg) was weighed out, addedto the die, and tamped slightly to flatten. Then, the core tablet wasplaced into the die and pressed down gently into the mantle blend. Thesecond half of the mantle blend (104.9 mg) was then added on top of thecore tablet, and the mantle was compressed using 1.5 MT force. The finalcompression coated tablets had a total weight of 314.7 mg with a(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate loading of100 mg (31.78%). The tablets had a final hardness around 13.1 kp (˜128Newtons).

Example 10 Composition of CCT Dosage Form (Non-Enteric Coated, 8% HPMCin Core)

Compression coated tablets containing (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate were made having the ingredients shownin Table 13:

TABLE 13 Composition of CCT Dosage Form (Non-Enteric Coated, 8% HPMC inCore) Quantity Quantity Component Manufacturer Role (mg/tablet) (% w/w)(N,N-Diethylcarbamoyl)methyl Cambridge Major Drug substance 100.0 27.59methyl (2E)but-2-ene- (Germantown, WI) 1,4-dioate HydroxypropylCellulose Aqualon (Hopewell, Binder 3.1 0.86 VA) Hypromellose 2208 DowChemical Sustained Release 9.1 2.51 (100000 mPa · s) (Midland, MI)Polymer Silicon Dioxide Evonik (Rheinfelden, Glidant 0.6 0.17 Germany)Magnesium Stearate Mallinckrodt (St. Lubricant 1.7 0.47 Louis, MO) TotalCore 114.5 31.59 Lactose Hydrate Foremost Filler 164.8 45.47(Rothschild, WI) Hypromellose 2208 Dow Chemical Sustained Release 80.622.24 (100 mPa · s) (Midland, MI) Polymer Magnesium StearateMallinckrodt (St. Lubricant 2.5 0.69 Louis, MO) Total Mantle 247.9 68.41Total Tablet 362.4 100.00

The tablets were made according to the following steps. The core tabletswere prepared using a wet granulation process. The granulation wasperformed in 2 batches at 494.88 g each. (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate was passed through a 1.0 mm mesh screen.Hydroxypropyl cellulose was passed through a 600 micron mesh screen.(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate andhydroxypropyl cellulose were combined in a 3 L bowl and mixed for 10minutes using the Quintech granulator. The mixture was then transferredto a 2 L bowl granulated with purified water using the Quintechgranulator. The wet granules were screened through a 2000 micron meshscreen and dried on trays in an oven at 30° C. for 4 hours 20 minutes.The dried granules were then passed through an 850 micron screen.

The core blend batch size was 1099.2 g. Thehydroxypropylmethyl-cellulose (i.e., Hypromellose 2208 having 100000mPa·s viscosity) and the silicon dioxide were combined, passed through a600 micron mesh screen, and added to the dry granules in a 5 L cubeblender and blended for 10 minutes at 25 rpm. Magnesium stearate waspassed through a 600 micron screen and added to the blend beforeblending an additional 4 minutes at 25 rpm. Core tablets (114.5 mg) werecompressed using a Manesty F3 tablet press with 6.0 mm round concavetooling. The core tablets had a final mean hardness between 8.1 to 10.2kp (79-100 Newtons).

The mantle blend was prepared using a direct compression process and abatch size of 5.0 kg. The hypromellose 2208 (100 MPa·s viscosity) andlactose hydrate were combined and passed through a 600 micron meshscreen, placed in and blended on the Tumblemix 18 L Bin Blender for 8.5minutes at 30 rpm. Magnesium stearate was passed through a 600 micronscreen and added to the blend and blended an additional 3.5 minutes. Themantle blend was then applied to the core tablets using a Kikusui tabletpress (Kikusui Seisakusho Ltd., Kyoto, Japan) specially designed for themanufacture of compression coated tablets. Compression was completedusing 9.5 mm round concave tooling and approximately 1000 kp force. Thefinal compression coated tablets had a total weight of 362.4 mg with a(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate loading of100 mg (27.59%). The compression coated tablets had a final meanhardness between 10.9 to 14.0 kp (107-137 Newtons).

Example 11 In Vitro Dissolution Profile of Compression Coated TabletDosage Forms

A two-stage dissolution method was used to determine the in vitrodissolution profile of dosage forms prepared according to Examples 8, 9,and 10 in order to mimic the conditions of a dosage form as it transitsthe gastrointestinal tract. Thus, the dosage forms were first placedinto a dissolution medium having a pH of 1.2, to mimic the conditions ofthe stomach, and then placed into a dissolution medium of pH 6.8, tomimic the conditions of the intestines. The dissolution vessel (USP,Type I, basket) initially contained 750 mL of 0.1 N hydrochloric acid(pH 1.2). After 2 hours of dissolution, 250 mL of 200 mM tribasic sodiumphosphate was added to the vessel resulting in a pH adjustment from 1.2to 6.8. The dissolution medium was kept at 37° C. and was agitated at100 rpm.

For the tested dosage forms, samples of the dissolution medium werewithdrawn at the indicated time points shown in the respective figures.The amount of (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate in the dissolution medium samples wasdetermined by reverse phase HPLC using a C18 column and a 7 minutegradient method according to Table 14 where Mobile Phase A is water/0.1%H₃PO₄ and Mobile Phase B is water/acetonitrile/H₃PO₄ (10/90/0.1 byvolume) with UV detection at 210 nm.

TABLE 14 HPLC Gradient Conditions Time (minute) % Mobile Phase A %Mobile Phase B 0 85 15 5 35 65 5.5 85 15 7 85 15

As shown in FIG. 5, for dosage forms prepared according to Example 8,drug release is delayed for approximately 2 hours, and thereafter thedrug is released gradually, reaching more than 90% released at 16 hours.

As shown in FIG. 6, for dosage forms prepared according to Example 9,drug release is delayed for approximately 2 hours, followed by near zeroorder release, reaching more than 90% released at 24 hours.

As shown in FIG. 7, for dosage forms prepared according to Example 10,drug release is delayed for approximately 2 hours, and thereafter thedrug is released gradually, reaching more than 90% released at 16 hours.

Example 12 Preparation of Compression Coated Tablet Dosage FormNon-Enteric Coated, 10% HPMC in the Core

To demonstrate the effect of increasing the percentage of sustainedrelease polymer in the core on the in vitro dissolution profile, twodifferent tablet formulations were made according to the procedureoutlined in Example 8, but with differing levels of hypromellose 2208(100000 MPa-s viscosity) in the core, i.e., compared to the Example 8tablets. Thus, the Example 8 tablets contained 8 wt % HPMC in the corewhile the Example 12 tablets contained 10 wt % HPMC in the core,respectively. The tablet formulations, including the Example 8 tabletformulation for reference, are shown in Table 15.

TABLE 15 Composition of CCT Dosage Forms (Non-Enteric Coated, 8% and 10%HPMC in Core) Quantity Quantity Quantity Quantity (mg/tablet) (% w/w)(mg/tablet) (% w/w) Component Example 8 Example 12(N,N-Diethylcarbamoyl) 100.00 29.19 100.00 28.55 methyl methyl(2E)but-2-ene-1,4-dioate Hydroxypropyl Cellulose 3.12 0.91 3.10 0.88Hypromellose 2208 9.14 2.67 11.67 3.33 (100000 mPa · s) Silicon Dioxide0.23 0.06 0.23 0.07 Magnesium Stearate 1.71 0.50 1.75 0.50 Total Core114.20 33.33 116.75 33.33 Lactose Hydrate 157.60 46.00 161.12 46.00Hypromellose 2208 68.52 20.00 70.05 20.00 (100 mPa · s) MagnesiumStearate 2.28 0.67 2.33 0.67 Total Mantle 228.40 66.67 233.50 66.67Total Tablet 342.60 100.00 350.25 100.00

The dissolution profiles from the three compression coated tablets weremeasured according to the method described in Example 11. FIG. 8 showsthat the MHF prodrug release rate slows with increasing percentage ofhypromellose 2208 (100000 mPa·s) in the core, but the initial delaybefore the start of prodrug release stays the same at approximately 2hours, likely due to the unchanged mantle layer.

Example 13 Preparation of Sustained Release Tablet Dosage Forms(Non-Enteric Coated)

To demonstrate the effect of increasing the viscosity of sustainedrelease polymer in the mantle on the in vitro dissolution profile,tablets were made with hypromellose 2208 of different viscosities in themantle: Example 13a (4000 mPa·s), and Example 13b (a combination of 100mPa·s and 4000 mPa·s to give an effective viscosity of ˜2000 mPa·s). Theformulation details are shown in Table 16.

TABLE 16 Composition of Sustained Release Tablet Dosage Forms(Non-Enteric Coated) Quantity Quantity Quantity Quantity (mg/tablet) (%w/w) (mg/tablet) (% w/w) Component Example 13a Example 13b(N,N-Diethylcarbamoyl) 200.00 32.00 200.00 32.00 methyl methyl (2E)but-2-ene-1,4-dioate Hydroxypropyl Cellulose 6.20 1.00 6.20 1.00 MagnesiumStearate 2.10 0.30 2.10 0.30 Total Core 208.30 33.30 208.30 33.30Lactose Hydrate 308.30 49.30 308.30 49.30 Hypromellose 2208 0.00 0.0052.05 8.35 (100 mPa · s) Hypromellose 2208 (4000 mPa · s) 104.10 16.7052.05 8.35 Magnesium Stearate 4.20 0.70 4.20 0.70 Total Mantle 416.6066.70 416.60 66.70 Total Tablet 624.90 100.00 624.90 100.00

The tablets were made according to the following steps. The core tabletswere prepared using a wet granulation process. The granulation batchsize was 170 g. (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate was passed through the Quadro Comil U5 with an813 micron screen at 2000 rpm. Hydroxypropyl cellulose was passedthrough a 500 micron mesh screen. (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate and hydroxypropyl cellulose were granulatedwith purified water using a Diosna P1/6 equipped with a 1 L bowl. Thewet granules were screened through an 1180 micron mesh screen and driedon trays in an oven at 30° C. for 3 hours 48 minutes.

The core blend batch size was 20.0 g. The dried granules and magnesiumstearate were combined in a glass bottle and blended in a Turbula mixerfor 2 minutes. Core tablets (208.3 mg) were compressed using a ManestyFlexiTab single station tablet press with 5/16 inch (7.9 mm) roundstandard concave tooling at forces ranging from 9.9 to 14.0 kN. The coretablets had a final mean hardness of 8.4 kp (˜82 Newtons).

The mantle blend was prepared using a direct compression process and abatch size of either 10 g (Example 13b) or 20 g (Example 13a). Thehypromellose 2208 and lactose hydrate were passed through a 600 micronmesh screen, combined in a glass bottle and blended in a Turbula mixerfor either 10 (Example 13a), or 5 (Example 13b) minutes. In each case,magnesium stearate was passed through a 250 micron screen and added tothe blend and blended an additional 1.5 minutes. The mantle blend wasthen applied to the core tablets using the Carver Press with 7/16 inch(11.1 mm) round standard concave tooling. Half the mantle blend (208.3mg) was weighed out, added to the die, and tamped slightly to flatten.Then, the core tablet was placed into the die and pressed down gentlyinto the mantle blend. The second half of the mantle blend (208.3 mg)was then added on top of the core tablet and the mantle was compressedusing 2.0 metric ton (MT) force. The final compression coated tabletshad a total weight of 624.9 mg with a (N,N-Diethylcarbamoyl)methylmethyl (2E)but-2-ene-1,4-dioate loading of 200 mg (32.00%). The tabletshad a final hardness of about 18.3 to 19.5 kp (179 to 191 Newtons).

The dissolution profiles from the two compression coated tablets weremeasured according to the method described in Example 11. FIG. 9 showsthat the MHF prodrug release rate slows with increasing hypromelloseviscosity and the delay time increases slightly with increasinghypromellose viscosity.

Example 14 Preparation of Sustained Release Tablet Dosage FormsNon-Enteric Coated with 5 wt % Hypromellose 2208 (100000 mPa·s) in theCore and 40% Hypromellose 2208 (100 MPa·s) in the Mantle

To demonstrate the effect of increasing the percentage of hypromellose2208 (100 mPa·s viscosity) in the mantle on the in vitro dissolutionprofile and reducing the amount of hypromellose 2208 (100000 mPa·s) inthe core, tablets were made according to the procedure outlined inExample 8, but with 5 wt % hypromellose 2208 (100000 mPa·s) in the coreand 40% of hypromellose 2208 (100 MPa-s) in the mantle: The tabletformulation is shown in Table 17.

TABLE 17 Composition of SR Tablet Dosage Forms [Non-Enteric Coated with5 wt % hypromellose 2208 (100000 mPa · s) in the core and 40%hypromellose 2208 (100 MPa · s) in the mantle] Quantity Quantity(mg/tablet) (% w/w) Component Example 14 (N,N-Diethylcarbamoyl)methylmethyl 100.00 30.17 (2E)but-2-ene-1,4-dioate Hydroxypropyl Cellulose3.10 0.93 Hypromellose 2208 5.52 1.66 (100000 mPa · s) Silicon Dioxide0.22 0.07 Magnesium Stearate 1.66 0.50 Total Core 110.50 33.33 LactoseHydrate 130.39 39.33 Hypromellose 2208 88.40 26.67 (100 mPa · s)Magnesium Stearate 2.21 0.67 Total Mantle 221.00 66.67 Total Tablet331.50 100.00

The dissolution profile from the Example 14 compression coated tabletswas measured according to the method described in Example 11. FIG. 10shows that the delay to drug release is increased with increasingpercentage of hypromellose 2208 (100 mPa·s) in the mantle, and the rateof MHS prodrug increases slightly with decreasing percentage ofhypromellose 2208 (100000 mPa·s) in the core.

Example 15 Preparation of Sustained Release Tablet Dosage FormsNon-Enteric Coated Formulation with No Hypromellose in the Core and ThinMantle

To demonstrate the effect of decreasing the thickness of the mantle onthe in vitro dissolution profile, the mantle to core weight ratio wasdecreased from 2 to 1.5. The tablet formulation is shown in Table 18.

TABLE 18 Composition of SR Tablet Dosage Form (Non-Enteric Coated)Quantity Quantity (mg/tablet) (% w/w) Component Example 15(N,N-Diethylcarbamoyl)methyl methyl 100.00 38.37(2E)but-2-ene-1,4-dioate Hydroxypropyl Cellulose 3.06 1.17 SiliconDioxide 0.10 0.04 Magnesium Stearate 1.04 0.40 Total Core 104.20 40.00Lactose Hydrate 107.8 41.40 Hypromellose 2208 46.9 18.00 (100000 mPa ·s) Magnesium Stearate 1.56 0.60 Total Mantle 156.40 66.70 Total Tablet260.60 100.00

The tablets were made according to the following steps. The core tabletswere prepared using a wet granulation process. The granulation batchsize was 680 g. (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate was passed through the Quadro Comil U5 with an813 micron screen at 2000 rpm. Hydroxypropyl cellulose was passedthrough a 600 micron mesh screen. (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate and hydroxypropyl cellulose were granulatedwith purified water using a Diosna P1/6 equipped with a 4 L bowl. Thewet granules were screened through an 1180 micron mesh screen and driedon trays in an oven at 30° C. for 6 hours.

The core blend batch size was 30.0 g. The dried granules and the silicondioxide were then passed through a 600 micron mesh screen, combined in aglass jar and blended in a Turbula mixer for 2 minutes. Magnesiumstearate was passed through a 250 micron screen and added to the blendbefore blending an additional 1.5 minutes. Core tablets (104.2 mg) werecompressed using a Manesty FlexiTab single station tablet press with ¼inch (6.35 mm) round standard concave tooling at approximately 3 kNforce. The core tablets had a final hardness of 6.2 to 7.0 kp (about 61to 69 Newtons).

The mantle blend was prepared using a direct compression process and abatch size of 10 g. The hypromellose 2208 (100000 MPa-s) and lactosehydrate were passed through a 600 micron mesh screen, combined in aglass bottle and blended for 5 minutes in a Turbula mixer. Magnesiumstearate was passed through a 250 micron screen and added to the blendand blended an additional 1.5 minutes. The mantle blend was then appliedto the core tablets using the Carver Press with 5/16 inch (7.94 mm)round standard concave tooling. Half the mantle blend (78.2 mg) wasweighed out, added to the die, and tamped slightly to flatten. Then, thecore tablet was placed into the die and pressed down gently into themantle blend. The second half of the mantle blend (78.2 mg) was thenadded on top of the core tablet and the mantle was compressed using 1.1metric ton (MT) force. The final compression coated tablets had a totalweight of 260.6 mg with a (N,N-Diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate loading of 100 mg (38.37%). The tablets had afinal hardness ranging from 13.1 to 14.0 kp (about 128 to 137 Newtons).

The dissolution profile from the compression coated tablets was measuredaccording to the method described in Example 11. FIG. 11 shows that therelease of drug substance from the tablet increases with decreasingmantle to core weight ratio (compare with Example 9 and FIG. 6).

Example 16 Safety, Tolerability, and Pharmacokinetics of Example 10Dosage Form

A randomized, double-blind crossover, food effect, single-dose study ofthe safety, tolerability, and pharmacokinetics of an oral dosage form of(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate in healthyadult subjects was conducted. Twelve healthy adult volunteers (males andfemales) participated in the study. All twelve subjects received adosage form of Example 10, once in a fed condition and once in a fastedcondition, with a two-week washout between treatments. The fasted dosingwas achieved by dosing the subject following an overnight fast while thefed dosing was achieved by dosing the subject after consuming a highfat-content breakfast. The dosage form contained 100 mg of(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate (54 mgequivalents of methyl hydrogen fumarate).

Blood samples were collected from all subjects prior to dosing, and at0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 30, 36, 48, 60, 72,84, 96, 108 and 120 hours after dosing. Urine samples were collectedfrom all subjects prior to dosing, and complete urine output wasobtained at the 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96 and96-120 hour intervals after dosing. Blood samples were quenchedimmediately with acetonitrile and frozen. Sample aliquots were preparedfor analysis of (i) methyl hydrogen fumarate, (ii)(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, (iii) N,Ndiethyl-2-hydroxy acetamide and (iv)(2S,3S,4S,5R,6R)-6-[(N,N-diethylcarbamoyl)methoxy]-3,4,5-trihydroxy-2H-3,4,5,6-tetrahydropyran-2-carboxylicacid, the latter two being other potential metaboliltes of(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, usingsensitive and specific LC/MS/MS methods.

The plasma concentration of MMF following oral dosing of the formulationprepared according to Example 10 to fasted and fed healthy adultpatients is shown in FIG. 12. Table 19 shows the preliminary mean (SD)pharmacokinetic data for (N,N-diethylcarbamoyl)methyl methyl(2E)but-2-ene-1,4-dioate in fed and fasted patients.

TABLE 19 PK Data for Example 10 Dosage Form Average C_(max) AUC_(inf) NFood (ng/mL) (ng · hr/mL) 12 Fasted 143 625 (61.1) (216) 12 Fed 217 750(88.5) (242)

MMF release from the formulation was sustained and minimally affected byfood. The formulation produced mean (SD) maximum MMF concentrations(average Cmax) 143 (61) ng/mL fasted and 217 (89) ng/mL fed. MMF AUC was625 (216) ng·h/mL fasted and 750 (242) ng·h/mL fed. Promoiety wascleared from blood with a half-life around 3 hours.(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate was welltolerated during the trial. All 12 subjects completed the dosing period.All adverse events were mild. Adverse events that were reported in morethan one subject and that were more frequently for(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate than forplacebo were flushing and feeling hot. A comparison of these adverseevents to placebo is shown in Table 20.

TABLE 20 Comparison of Adverse Events Flushing Feeling Hot Fasted FedFasted Fed Placebo 0 1 0 0 Formulation 0 1 0 0

Finally, it should be noted that there are alternative ways ofimplementing the embodiments disclosed herein. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive,and the claims are not to be limited to the details given herein, butmay be modified within the scope and equivalents thereof.

1. A method of systemically administering a therapeutically effectiveamount of a compound selected from (i) monomethyl fumarate (MMF), (ii) aprodrug of monomethyl fumarate, and (iii) a combination thereof, totreat a disease in each patient of a population of patients in need ofsuch treatment, comprising administering the compound(s) to each patientto achieve across the population a maximum average concentration ofmonomethyl fumarate in the blood plasma of the patients of less than 500ng/ml.
 2. The method of claim 1, wherein the maximum averageconcentration of monomethyl fumarate in the blood plasma of the patientsis less than 400 ng/ml.
 3. A method of systemically administering atherapeutically effective amount of a compound selected from (i)monomethyl fumarate (MMF), (ii) a prodrug of monomethyl fumarate, and(iii) a combination thereof, to treat a disease in each patient of apopulation of patients in need of such treatment, comprisingadministering the compound(s) to each patient to achieve across thepopulation an average Cmax of monomethyl fumarate in the blood plasma ofthe patients of less than 1100 ng/ml.
 4. The method of claim 3, whereinthe average Cmax of monomethyl fumarate in the blood plasma of thepatients is less than 600 ng/ml.
 5. A method of systemicallyadministering a therapeutically effective amount of a compound selectedfrom (i) monomethyl fumarate (MMF), (ii) a prodrug of monomethylfumarate, and (iii) a combination thereof, to treat a disease in eachpatient of a population of patients in need of such treatment,comprising administering the compound(s) to each patient to achieveacross the population an average maximum rate of rise in monomethylfumarate concentration in the blood plasma of the patients of less than0.25 wt % ng-eq of MMF dosed/ml/hr.
 6. The method of claim 5, whereinthe average maximum rate of rise in monomethyl fumarate concentration inthe blood plasma of the patients is less than 0.20 wt % ng-eq of MMFdosed/ml/hr or is less than 0.15 wt % ng-eq of MMF dosed/ml/hr.
 7. Themethod of claim 5, wherein the average maximum rate of rise inmonomethyl fumarate concentration in the blood plasma of the patients isless than 0.10 wt % ng-eq of MMF dosed/ml/hr
 8. The method of claim 5,wherein the average maximum rate of rise in monomethyl fumarateconcentration is less than 500 ng/mL/hr.
 9. The method of claim 5,wherein the average maximum rate of rise in monomethyl fumarateconcentration is less than 400 ng/mL/hr.
 10. The method of claim 1,wherein incidence of flushing in the population of patients is reduced.11. The method of claim 1, wherein the disease is selected from multiplesclerosis and psoriasis.
 12. The method of claim 1, wherein the diseaseis selected from adrenal leukodystrophy, AGE-induced genome damage,Alexanders Disease, Alper's Disease, Alzheimer's disease, amyotrophiclateral sclerosis, angina pectoris, arthritis, asthma, balo concentricsclerosis, Canavan disease, cardiac insufficiency including leftventricular insufficiency, central nervous system vasculitis,Charcott-Marie-Tooth Disease, childhood ataxia with central nervoussystem hypomyelination, chronic idiopathic peripheral neuropathy,chronic obstructive pulmonary disease, Crohn's disease, diabeticretinopathy, graft versus host disease, hepatitis C viral infection,herpes simplex viral infection, human immunodeficiency viral infection,Huntington's disease, irritable bowel disorder, ischemia, KrabbeDisease, lichen planus, macular degeneration, mitochondrialencephalomyopathy, monomelic amyotrophy, multiple sclerosis, myocardialinfarction, neurodegeneration with brain iron accumulation,neuromyelitis optica, neurosarcoidosis, NF-κB mediated diseases, opticneuritis, pareneoplastic syndromes, Parkinson's disease,Pelizaeus-Merzbacher disease, primary lateral sclerosis, progressivesupranuclear palsy, psoriasis, reperfusion injury, retinopathiapigmentosa, Schilders Disease, subacute necrotizing myelopathy, susacsyndrome, transplantation rejection, transverse myelitis, a tumor,ulcerative colitis, Zellweger's syndrome, granulomas includingannulaire, pemphigus, bollus pemphigoid, behcet's, contact dermatitis,acute dermatitis, chronic dermatitis, alopecia areata (totalis anduniversalis), sarcoidosis, cutaneous sarcoidosis, pyoderma gangrenosum,cutaneous lupus, Crohn's disease and cutaneous Crohn's disease.
 13. Themethod of claim 1, wherein the compound comprises monomethyl fumarate.14. The method of claim 1, wherein the compound comprises a prodrug ofmonomethyl fumarate.
 15. The method of claim 14, wherein the compoundcomprises a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ is C₁₋₆ alkyl.16. The method of claim 15, wherein the compound comprises dimethylfumarate.
 17. The method of claim 1, wherein the compound is a compoundof Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: R² and R³ areindependently chosen from hydrogen, C₁₋₆ alkyl, and substituted C₁₋₆alkyl; R⁴ and R⁵ are independently chosen from hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₁₋₆ alkoxy, substituted C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, substituted C₁₋₆ alkoxycarbonyl, C₁₋₆ heteroalkyl,substituted C₁₋₆ heteroalkyl, C₄₋₁₂ cycloalkylalkyl, substituted C₄₋₁₂cycloalkylalkyl, C₇₋₁₂ arylalkyl, and substituted C₇₋₁₂ arylalkyl; or R⁴and R⁵ together with the nitrogen to which they are bonded form a ringchosen from a C₅₋₁₀ heteroaryl, substituted C₅₋₁₀ heteroaryl, C₅₋₁₀heterocycloalkyl, and substituted C₅₋₁₀ heterocycloalkyl; wherein eachsubstituent group is independently chosen from halogen, —OH, —CN, —CF₃,═O, —NO₂, benzyl, —C(O)NR¹¹ ₂, —R¹¹, —OR¹¹, —C(O)R¹¹, —COOR¹¹, and —NR¹¹₂ wherein each R¹¹ is independently chosen from hydrogen and C₁₋₄ alkyl.18. The method of claim 17, wherein the compound is chosen from:(N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate; methyl2-morpholin-4-yl-2-oxoethyl (2E)but-2-ene-1,4-dioate; andpharmaceutically acceptable salts thereof.
 19. The method of claim 1,wherein the compound is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein: R⁶ is chosenfrom C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₁₋₆ heteroalkyl, substitutedC₁₋₆ heteroalkyl, C₃₋₈ cycloalkyl, substituted C₃₋₈ cycloalkyl, C₆₋₈aryl, substituted C₆₋₈ aryl, and —OR¹⁰ wherein R¹⁰ is chosen from C₁₋₆alkyl, substituted C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, substituted C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, and substituted C₆₋₁₀ aryl; R⁷ and R⁸ areindependently chosen from hydrogen, C₁₋₆ alkyl, and substituted C₁₋₆alkyl; and wherein each substituent group is independently chosen fromhalogen, —OH, —CN, —CF₃, ═O, —NO₂, benzyl, —C(O)NR¹¹ ₂, —R¹¹, —OR¹¹,—C(O)R¹¹, —COOR¹¹, N(R¹¹)C(O)C(R¹¹)₂NR¹¹ ₂, and —NR¹¹ ₂ wherein each R¹¹is independently chosen from hydrogen and C₁₋₄ alkyl.
 20. The method ofclaim 19, wherein the compound is chosen from: 1-(ethoxycarbonyloxy)ethyl methyl (2E)but-2-ene-1,4-dioate; methyl1-(methylethoxycarbonyloxy)ethyl (2E)but-2-ene-1,4-dioate; methyl1-(2-methylpropanoyloxy)ethyl (2E)but-2-ene-1,4-dioate; methyl1-(phenylcarbonyloxy)ethyl (2E)but-2-ene-1,4-dioate;cyclohexylcarbonyloxybutyl methyl (2E)but-2-ene-1,4-dioate;[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethyl methyl(2E)but-2-ene-1,4-dioate; 1-(cyclohexyloxycarbonyloxy)ethyl methyl(2E)but-2-ene-1,4-dioate; methyl 2-methyl-1-phenylcarbonyloxypropyl(2E)but-2-ene-1,4-dioate;3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-aminopropanoicacid;3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-aminopropanoicacid;3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-(2-aminoacetylamino)propanoicacid;3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(2S)-2-(aminoacetylamino)propanoicacid;3-1-{{[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethoxycarbonyl}}(2S)-2-aminopropanoicacid; and a pharmaceutically acceptable salt of any of the foregoing.21. The method of claim 1, wherein the compound is a compound of Formula(IV):

or a pharmaceutically acceptable salt thereof, wherein n is an integerfrom 2 to
 6. 22. The method of claim 21, wherein the compound is chosenfrom: methyl 2-morpholin-4-ylethyl (2E)but-2-ene-1,4-dioate; methyl3-morpholin-4-ylpropyl (2E)but-2-ene-1,4-dioate; methyl4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate; and a pharmaceuticallyacceptable salt of any of the foregoing.
 23. A method of systemicallyadministering a therapeutically effective amount of a compound selectedfrom (i) monomethyl fumarate (MMF), (ii) a prodrug of monomethylfumarate, and (iii) a combination thereof, to treat a disease in apatient in need of such treatment, comprising one of a) or b): a) orallyadministering to the patient, at a dosing frequency of not more thantwice per day, an enteric-coated oral sustained release dosage formcontaining a therapeutically effective dose of the compound(s), whereinthe dosage form, when subjected to an in vitro dissolution testemploying as a dissolution medium 750 mL of 0.1 N hydrochloric acid, atpH 1.2, for a period of 2 hours, followed by addition of 250 mL of 200mM tribasic sodium phosphate buffer resulting in an adjustment of the pHof the dissolution medium to 6.8, the dissolution medium beingmaintained at 37° C. and stirred at 100 rpm, releases: (i) less than 10wt % of the dose over an initial 2 hours of the in vitro dissolutiontest; (ii) at least 90 wt % of the dose over not less than an initial 8hours of the in vitro dissolution test; (iii) no more than 30 wt % ofthe dose in any one hour during the in vitro dissolution test; and (iv)no more than 40 wt % of the dose in any consecutive two hours during thein vitro dissolution test; or b) orally administering to the patient, ata frequency of not more than twice per day, a non-enteric-coated oralsustained release dosage form containing a therapeutically effectivedose of the compound(s), wherein the dosage form, when subjected to anin vitro dissolution test employing as a dissolution medium 750 mL of0.1 N hydrochloric acid, at pH 1.2, for a period of 2 hours, followed byaddition of 250 mL of 200 mM tribasic sodium phosphate buffer resultingin an adjustment of the pH of the dissolution medium to 6.8, releases(i) at least 90 wt % of the dose over not less than an initial 8 hoursof the in vitro dissolution test; (ii) no more than 30 wt % of the dosein any one hour during the in vitro dissolution test; and (iii) no morethan 40 wt % of the dose in any consecutive two hours during the invitro dissolution test.
 24. The method of claim 23, wherein the dosingfrequency is twice per day.
 25. The method of claim 23, wherein thedosing frequency is once per day.
 26. The method of claim 25, whereinthe dosage form releases at least 90 wt % of the dose over not less thanan initial 10 hours of the in vitro dissolution test.